Annu. Rev. Pharmacol. Toxicol. 1997. 37:205–37
Copyright c 1997 by Annual Reviews Inc. All rights reserved
PHARMACOLOGY AND FUNCTIONS
OF METABOTROPIC GLUTAMATE
RECEPTORS
P. Jeffrey Conn1 and Jean-Philippe Pin2
1 Department
of Pharmacology, Emory University School of Medicine, Atlanta,
Georgia 30322, pconn@emory.edu
2 UPR CNRS 9023 “Mécanismes Moléculaires des Communications Cellulaires,”
CCIPE, rue de la Cardonille, 34094 Montpellier Cedex 5, France,
pin@ccipe.montp.inserm.fr
KEY WORDS:
mGluRs, G-protein-coupled receptors, neuromodulation
ABSTRACT
In the mid to late 1980s, studies were published that provided the first evidence for
the existence of glutamate receptors that are not ligand-gated cation channels but
are coupled to effector systems through GTP-binding proteins. Since those initial
reports, tremendous progress has been made in characterizing these metabotropic
glutamate receptors (mGluRs), including cloning and characterization of cDNA
that encodes a family of eight mGluR subtypes, several of which have multiple splice variants. Also, tremendous progress has been made in developing
new highly selective mGluR agonists and antagonists and toward determining
the physiologic roles of the mGluRs in mammalian brain. These findings have
exciting implications for drug development and suggest that the mGluRs provide
a novel target for development of therepeutic agents that could have a significant
impact on neuropharmacology.
INTRODUCTION
Glutamate is the transmitter of the vast majority of the fast excitatory synapses in
the mammalian CNS and plays an important role in a wide variety of CNS functions (see 1 for review). Until recently, the actions of glutamate in mammalian
brain were thought to be mediated exclusively by activation of glutamate-gated
cation channels termed ionotropic glutamate receptors (iGluRs). Modulation of
205
0362-1642/97/0415-0205$08.00
206
CONN & PIN
transmission through glutamatergic circuits was thought to require neuromodulators from extrinsic afferents (e.g. dopamine, acetylcholine, serotonin, and
norepinephrine) that modulate synaptic transmission and cell excitabiltiy by activating GTP-binding protein (G-protein)–linked receptors. In the mid 1980s,
however, evidence for the existence of glutamate receptors directly coupled to
second messenger systems via G-proteins began to appear with the discovery of
glutamate receptors coupled to activation of phosphoinositide hydrolysis (2, 3).
Since that time, it has become clear that glutamate activates a large family of
receptors, termed metabotropic glutamate receptors (mGluRs), that are coupled
to effector systems through GTP-binding proteins.
The discovery of mGluRs dramatically altered the traditional view of glutamatergic neurotransmission since activation of mGluRs can modulate activity in
glutamatergic circuits in a manner previously associated only with neuromodulators from nonglutamatergic afferents. Unlike receptors for monoamines and
other neuromodulators, however, the mGluRs provide a mechanism by which
glutamate can modulate or fine-tune activity at the same synapses at which it
elicits fast synaptic responses. Because of the ubiquitous distribution of glutamatergic synapses, mGluRs have the potential to participate in a wide variety
of functions of the CNS. In addition, the wide diversity and heterogeneous
distribution of mGluR subtypes provide an opportunity for developing pharmacologic agents that selectively interact with mGluRs involved in only one or a
limited number of CNS functions. Thus, gaining a detailed understanding of
the specific roles of mGluRs could have a dramatic impact on development of
novel treatment strategies for a variety of psychiatric and neurologic disorders.
CLONED mGLURS: CLASSIFICATION
Cloning of mGluRs: Multiplicity Caused by Several
Genes and Alternative Splicing
The first mGluR cDNA was cloned independently by two groups that used
the same functional expression assay and is now generaly named mGluR1a
(4, 5) (see below for the mGluR nomenclature). Its deduced amino acid sequence revealed that this receptor shares no sequence homology with any other
G-protein coupled receptor (GPCR), which suggests that it could be a member
of a new receptor gene family. Moreover, pharmacologic studies suggested the
existence of several G-protein coupled glutamate receptors (6). The search for
mGluR-related cDNA has now resulted in the isolation of seven other genes and
several splice variants that encode mGluRs (7–17). These receptors are named
mGluR1 through mGluR8 (Figure 1).
As mentioned above, splice variants have been found for three mGluRs:
mGluR1, mGluR4, and mGluR5 (Figure 2) (7, 8, 14, 16). All these variants
METABOTROPIC GLUTAMATE RECEPTORS
207
Figure 1 Dendrogram and pharmacologic classification of the members of the mGluR family,
including the Drosphila mGluR (DmGluRA) and the bovine parathyroid Ca2+ -sensing receptor
(PCaR).
Figure 2 Schematic representation of the sequences of the mGluR splice variants characterized
to date. The coding sequences are represented as white boxes, the 7 TMDs correspond to the black
squares. The untranslated regions are indicated by horizontal lines. Identical sequences found in
the different variants derived from the same gene are joined by dashed lines. Only the introns that
may be involved in the generation of these splice variants are presented (V).
208
CONN & PIN
result from the use of alternative acceptor splice sites in an intron whose position
is conserved at least between these three genes. mGluR1b, mGluR1c, and
mGluR1d lack the long carboxyl-terminal domain specific for mGluR1a. In
rat mGluR1b, mGluR1c, and mGluR1d, the carboxyl terminal 318 residues of
mGluR1a are replaced by 20 (7), 11 (8), and 26 (D Stephan & R Pruss, personal
communication) residues or 22 residues for human mGluR1d (HmGluR1d)
(17). Compared with mGluR5a, mGluR5b contains an insertion of 32 amino
acids, 50 residues after the seventh transmembrane domain (TMD) (13, 14).
The carboxyl-terminal 63 residues of mGluR4a are replaced by 136 residues in
mGluR4b (16).
To date, the human homologues of mGluR1a, b, and d (17, 18), mGluR2
(19), mGluR3 (20), mGluR4a (21), mGluR5a and b (14, 22) have been cloned.
The primary sequence of the human receptors show 93–96% identity compared
with the rat homologues. A metabotropic glutamate receptor called DmGluRA
has also been cloned from Drosophila melanogaster (22a). It shows a high
homology with the mammalian group II mGluRs (45% identity of the amino
acid sequence with mGluR3) (Figure 1).
Based on their amino acid sequence identity, the eight mGluRs can be classified into three groups (Figure 1) (23). mGluRs of the same group show about
70% sequence identity, whereas between groups this percentage decreases to
about 45%. Group I includes mGluR1 and mGluR5; group II, mGluR2 and
mGluR3; and group III, all others. The Drosophila receptor DmGluRA is more
related to group II mammalian mGluRs (Figure 1).
These receptors are much larger than all previously identified GPCRs and
do not share any sequence homology with members of that gene superfamily.
mGluRs therefore define a new family of GPCRs. Three years ago, a Ca2+ sensing receptor (CaR) cDNA was isolated from a bovine parathyroid cDNA
library. It has a surprisingly high homology (30% sequence identity) with
mGluRs (24). This receptor is not sensitive to mGluR agonists but is sensitive
to other cations, such as Mg2+ , Gd3+ , and to neomycin. The rat and human
homologues of CaR have been cloned and display 92 and 93% identity with the
bovine receptor (25–27). This indicates that this new family of GPCR is not
restricted to glutamate receptors and may include additional members sensitive
to other ions or transmitters.
Transduction Mechanisms of mGluRs Expressed
in Heterologous Systems
As already presented, mGluRs can be subdivided into three groups based on the
homology of their amino acid sequences. This classification is also supported
by the respective transduction mechanisms of the different mGluR subtypes
(Figure 1).
METABOTROPIC GLUTAMATE RECEPTORS
209
In every expression system examined, group I mGluRs, including their splice
variants, stimulate phospholipase C and phosphoinositide (PI) hydrolysis (4,
5, 8, 9, 13, 14, 17, 18, 22). Coupling of mGluR1a to ion channels has also
been examined after injection of its cRNA into superior cervical ganglion neurons, where this receptor can inhibit M-type K+ channels (28). It is not clear,
however, whether this is mediated by direct coupling through a G-protein to
the M-type channel or is secondary to activation of phosphoinositide hydrolysis. Stimulation of cAMP formation has also been reported for mGluR1a in
several cell types (13, 29–31). A similar effect of mGluR5a and mGluR5b has
also been reported in LLC-PK1 cells (13) but not in CHO cells (9). Although
a direct coupling to adenylyl cyclase (AC) through GS -protein is likely (32),
this has not been definitively demonstrated. Moreover, whether this is an heterologous coupling caused by the expression of these receptors at high levels
in non-neuronal cells or is reminiscent of a low G-protein selectivity of these
receptors that is also true in neurons remains to be elucidated.
As described above, alternative splicing of group I mGluR pre-mRNA generates receptors with different intracellular carboxyl-terminal domains. When
expressed into mammalian cells, no functional differences between mGluR5a
and mGluR5b were noticed (13, 14). However, a role of the mGluR5b cassette in
controlling G-protein coupling specificity has been proposed (14). Functional
differences have been reported between the mGluR1a variant that possesses the
long carboxyl-terminal intracellular tail and the truncated isoforms mGluR1b
and mGluR1c. Compared with the short receptors, mGluR1a generates faster
responses in Xenopus oocytes (8), can activate AC (13, 30, 31), and is slightly
active even in the absence of agonist (33). Two explanations can be proposed for
these functional differences. Either the differences are caused by a difference in
the level of expression of these different receptors in these heterologous expression systems, mGluR1a being expressed at a higher level than the short receptors
mGluR1b or mGluR1c, or they are caused by a difference in the coupling efficiency of these receptors to the G-proteins. Estimation of the level of expression
of the different variants by Western blot and immunofluorescence, along with
indirect functional evidence, suggests that the long carboxyl-terminal domain
of mGluR1a increases the coupling efficiency of the receptor (8, 33).
When expressed in mammalian cells, group II mGluRs (mGluR2, mGluR3,
and the Drosophila homologue DmGluRA) inhibit cAMP formation stimulated
by either forskolin or a GS -coupled receptor (7, 22a, 34). This effect is inhibited
by pertussis toxin (PTX) treatment of the cells, which indicates the involvement
of a Gi -type of G-protein. Inhibition of N-type Ca2+ channels through a PTXsensitive pathway by mGluR2 has also been demonstrated after expression
of this receptor in superior cervical ganglion neurons (28) or HEK-293 cells
that stably express the N-type Ca2+ channels (human α1B-1, α2b, and β1-3
210
CONN & PIN
subunits) (35). Like mGluR2, mGluR3 inhibits N-type Ca2+ channels in these
HEK 293 cells (35).
Like group II mGluRs, all group III mGluRs inhibit adenylyl cyclase via a
PTX-sensitive G-protein when expressed in CHO or BHK cells (10–12, 15, 34).
The inhibition observed, however, is often smaller than that obtained with group
II mGluRs, which suggests either that group III mGluRs are not expressed at
very high density in the plasma membrane of these cell lines or that this is not
the preferred transduction pathway of these receptors. The second hypothesis
seems likely because mGluR6 is likely to couple to a cGMP phosphoidiesterase
in its native environment (36; see below). Moreover, coupling of mGluR7 to
heterogenously expressed G-protein-activated inwardly rectifying potassium
channel has been reported in Xenopus oocytes (37).
Pharmacology of Cloned mGluRs
Glutamate is a very flexible molecule that can adopt different conformations.
Several derivatives of glutamate, including rigid analogues, have therefore been
synthesized with the hope of discriminating among the different glutamate receptors. To date, there are several molecules that can be used to activate or
antagonize mGluRs of the different groups specifically (Figure 1). In this chapter, we review our actual knowledge of the pharmacology of typical members
of each mGluR group (mGluR1, mGluR2, and mGluR4, respectively) and describe the pharmacologic differences among members in each group. We have
concentrated on the pharmacology of cloned mGluRs expressed in heterologous
systems, because this is the only way to characterize the activity of compounds
on a specific mGluR subtype. Not only may several mGluRs be involved in a
response observed in the brain, it is not likely that all the mGluRs have already
been cloned. We use this information to try to identify the mGluR subtypes
involved in a given physiologic response. Focusing on cloned receptors expressed in heterologous systems has, however, two main disadvantages. First,
the potencies measured in these expression systems may not necessarily be
identical to those in the native environment of the receptor. Second, many new
promising compounds that have been recently described are not presented here
because their actions on cloned receptors have not been reported (38–40).
GROUP I mGLURs The pharmacologic profile of group I mGluRs has been
primarily studied with the use of mGluR1a as a prototypic member. Several
agonists have been characterized, and their rank order of potency is as follows: quisqualate >3, 5-dihydroxyphenylglycine (3, 5-DHPG) glutamate >1S,
3R-1-amino-1, 3-cyclopentanedicarboxylate (ACPD) = ibotenate > (2S, 1’S,
2’S)-2-(carboxycyclopropyl)glycine (L-CCG-I) > 3-hydroxyphenylglycine (3HPG) > trans-azetidine-2, 4-dicarboxylate (t-ADA) (Table 1 and Figure 3).
Among these 3, 5-DHPG, 3-HPG, and t-ADA are specific agonists (although
METABOTROPIC GLUTAMATE RECEPTORS
211
Table 1 Potency (EC50 , IC50 , or Kb values in µM) of several compounds determined on cell lines that express
the indicated mGluR subtypea
mGluR1a mGluR5a mGluR2 mGluR3 mGluR4a mGluR6 mGluR7 mGluR8 Notes
Agonists
Glutamate
Quisqualate
Ibotenate
1S, 3R-ACPD
1S, 3S-ACPD
L-CCG-1
DCG-IV
2R, 4R-APDC
L-AP4
L-SOP
L-AP3
3-HPG
3, 5-DHPG
4C3HPG
t-ADA
CPAP4
9–13
0.2–3.0
10–60
10–80
>300
50
n.e.
—
n.e.
n.e.
Ant.
68–100
6.6
Ant.
190
—
Antagonists
MCPG
4C3HPG
3C4HPG
4CPG
MPPG
MSPG
MTPG
MCCG-I
MAP4
L-AP3
ABHD-I
AIDC
PCCG-IV
7HCCMA
ADPD
40–200
>200 100–1000
10–40 P. Ag. (?)
Ag.
300–400
—
Ag.
15–65
>500
Ag. (?)
>1000
n.e.
100
n.e.
—
250
>1000
n.e.
450
n.e.
—
84
n.e.
—
500
>1000
>1000
—
300
—
—
7
—
n.e.
n.e.
n.e.
8
2
—
n.e.
n.e.
n.e.
18,1
3–10
0.03–0.3
2–10
5–7
>300
—
n.e.
—
n.e.
—
Ant.
14–35
2
>300
30
—
4–20
>1000
35–250
18
13
0.3–0.4
0.3
3∗
n.e.
—
—
n.e.
n.e.
20–50
>1000
—
4–5
40
10–15
8
30
1
0.2
—
n.e.
—
—
—
—
—
—
—
3–20
100–1000
100–1000
≫300
50
9–50
>1000
—
0.4–1.2
2–5
—
n.e.
n.e.
n.e.
n.e.
0.6
16
>300
>300
300
—
—
—
—
0.9
2.7
—
—
—
—
—
—
1000
—
—
—
—
—
n.e.
—
160–500
>160
n.e.
—
n.e.
—
—
—
0.02
—
—
—
—
—
—
—
0.4
—
—
—
—
—
—
—
>1000
—
—
—
—
—
—
—
—
—
—
—
—
—
—
n.e.
n.e.
n.e.
n.e.
54
≫1000
n.e.
n.e.
90–190
—
—
n.e.
Ag.
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
n.e.
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
b
c
d
e
e
e
f
g
h
e
e
e
i
d
a
Values are taken from the following references: mGluRla (4, 5, 13, 29, 43, 45, 49–60, 63, 64), mGluR5a (9, 13, 22, 43, 45, 58,
63, 64), mGluR2 (7, 19, 44, 48, 50–54, 59, 60, 62–64), mGluR3 (34, 60, 65), mGluR4a (19, 34, 44, 46, 48, 50, 52, 53, 60, 62, 63,
66, 67), mGluR6 (10), mGluR7 (11, 12, 46), mGluR8 (15). n.e., no effect; —, not determined.
b
Agonist at AMPA receptors.
c
Also activates NMDA receptors.
d
Only tested on human clones.
e
The S-form is the active enantiomer.
f
Inactive on HmGluR1b, HmGluR5a, and also reported to be inactive on mGluRla.
g
The Z-form is the more potent enantiomer.
h
The (+) form is the more potent enantiomer.
i
Other less potent derivatives include the ethyl ester of 7-(hydroxyimino)cyclopropa[b]chromen-la-carboxylate, and the 7-(hydroxyimino)cyclopropa[b]chromen-la-N-phenyl-carboxamide.
212
CONN & PIN
Figure 3 Structure of the most selective agonists and antagonists of the representative members
of group I (mGluR1), group II (mGluR2), and group III (mGluR4) mGluRs.
less efficient than glutamate), as they have almost no effect on ionotropic receptors or on mGluR2 and mGluR4 (41–46). However, t-ADA has been reported
to have no effect on HmGluR1b and HmGluR5a (47) and has been described as
inactive on mGluR1a by others (42). Other agonists of mGluR1a are (2S, 1′ R,
2′ R)-2-(carboxycyclopropyl)glycine (L-CCG-II) (EC50 = 200 µM), homocysteate (HCA; partial agonist), homocysteine sulfinate (HCSA: EC50 = 300
µM) and the neurotoxin β-N-methylamino-L-alanine (BMAA; EC50 = 480
µM) (29, 48–50). The first antagonist described for mGluR1a was α-methyl4-carboxyphenylglycine (MCPG). Several derivatives of phenylglycine have
since been synthesized, and (S)-4-carboxyphenylglycine ((S)-4CPG) and (S)4-carboxy-3-hydroxyphenylglycine ((S)-4C3HPG) were found to be the most
potent competitive antagonists of this receptor (50–52). More recently, new
compounds with original structures were found to be even more potent than
these phenylglycine derivatives on mGluR1a but inactive on mGluR2 and
mGluR4. These include 1-aminoindan-1, 5-dicarboxylate (AIDC) (53) and 7(hydroxyimino) cyclopropa [b] chromen-1a-N,N-methyl, phenyl-carboxamide
(7HCCMA) (54) (Figure 3). Bromohomoibotenate (BrHIBO) has also been
METABOTROPIC GLUTAMATE RECEPTORS
213
described as another specific competitive antagonist of mGluR1a with a low potency, inactive on mGluR2 and mGluR4 (55). Another antagonist of mGluR1a
is (1RS, 2SR, 4RS, 7RS)-amino-bicyclo[2.2.1]heptane-dicarboxylate (ABHD-I),
a rigid analogue of ACPD (56). Although it has a low potency (300 µM), this
compound is interesting because of its totally rigid structure so that the relative
positions of the carboxyl and amino groups in the binding site are the same as
in solution and are perfectly known.
The pharmacologic profiles of the short mGluR1 variants (mGluR1b and
mGluR1c) are identical to those of mGluR1a. In many cases, EC50 values for
the short receptors are higher than those for the long form (30, 33, 57), either
because of a better expression or because of a better coupling efficiency of
mGluR1a resulting from the presence of the long carboxyl-terminal tail (57; see
above). The agonist rank order of potency of mGluR5a and b is similar to that
of mGluR1a; most agonists, other than glutamate, are three to ten times more
potent (9, 13). However, both rat and human mGluR5a, although antagonized
by MCPG, are much less sensitive to 4CPG and 4C3HPG than is mGluR1a
(43, 58). These latter compounds may therefore be useful for discriminating
between mGluR1- and mGluR5-mediated responses.
GROUP II mGLURs The agonist rank order of potency at the prototypic member
of group II mGluRs, mGluR2 is (2S, 1′ R, 2′ R, 3′ R)-2-(2, 3-dicarboxycyclopropyl)glycine (DCG-IV) = L-CCG-I > 2R, 4R-4-aminopyrrolidine-2, 4-dicarboxylate (APDC) > glutamate > 1S, 3S-ACPD = 1S, 3R-ACPD > 4C3HPG
> ibotenate (Table 1 and Figure 3). Among these, only 2R, 4R-APDC is a
specific group II agonist (although its effect on mGluR3 has not been reported
yet) (59), because DCG-IV is an agonist of N-methyl-D-aspartate (NMDA)
receptors (60); L-CCG-I is also active on mGluR1 and mGluR4, although with
a tenfold lower potency (44, 48). 1S, 3S-ACPD, which has been widely used as
a specific group II mGluR agonist, is also active on mGluR4, although with a
lower potency (44). In addition, 1S, 3S-ACPD induces PI hydrolysis and elicits
electrophysiologic responses thought to be mediated by group I mGluRs in
hippocampal slices (46, 61). This compound should therefore not be used as a
group II selective agonist. The group II mGluR agonist 4C3HPG is a very useful compound because of its antagonist action on mGluR1 and its lack of effect
on mGluR4 (50–52, 62). Several competitive antagonists for mGluR2 have
been reported. After the discovery of the antagonist action of MCPG, several
other phenylglycine derivatives were found to be competitive antagonists of this
receptor. Their rank order of potency is α-methyl-4-phosphonophenylglycine
(MPPG) > α-methyl-4-sulfonophenylglycine (MSPG) > α-methyl-4-tetrazoylphenylglycine (MTPG) (44, 63). More potent competitive and specific antagonists include α-methyl-L-CCG-I (MCCG-I) (44), 2S, 4S- 2-amino-4-(4, 4-
214
CONN & PIN
diphenylbut-1-yl)-pentane-1, 5-dioic acid (ADPD) (64) and (2S, 1′ S, 2′ S, 3′ R)2-(2′ -carboxy-3′ -phenylcyclopropyl) glycine (PCCG-IV) (63), the latter being
the most potent antagonist described so far for mGluR2 (Table 1 and Figure 3).
The pharmacology of mGluR3 is less well characterized but seems to be
very similar to that of mGluR2 (34, 65); the main difference is that quisqualate,
which is almost devoid of effect on mGluR2 (7, 19, 44), is relatively potent on
mGluR3 (34). Little is known about the antagonist pharmacology of mGluR3.
By measuring inhibition of N-type Ca-channels in HEK-293 cells, McCool and
colleagues (35) reported that MCPG is far less potent and that MCCG-I is more
potent on mGluR3 than on mGluR2. Taken together, these observations indicate
that it is possible to discriminate between responses mediated by mGluR2 and
mGluR3 and that more selective drugs able to discriminate between these two
receptors can be synthesized.
The pharmacology of mGluR4 is very different from that
of the other mGluRs. The rank order of potency of several agonists is L-amino4-phosphonobutyrate (L-AP4) > L-serine-O-phosphate (L-SOP) > glutamate
L-CCG-I > 1S, 3S-ACPD ≫ 1S, 3R-ACPD (Table 1 and Figure 3). L-AP4
and L-SOP are very specific for group III mGluRs, as they are inactive on any
other glutamate receptors. Several other L-AP4 derivatives have been described
as agonists of mGluR4, including Z-cyclopropyl-AP4 (Z-CPAP4), which is as
potent as L-AP4 (66) (Figure 3). Most mGluR1 and mGluR2 antagonists are
inactive on mGluR4, except MPPG, which appears to be slightly more potent on
mGluR4 than on mGluR2 (44, 63). α-methyl-L-amino-4-phosphonobutyrate
(MAP4) appears the more selective mGluR4 antagonist; however, it is also an
antagonist with low potency on mGluR2 (44, 67) (Figure 3).
The pharmacology of the other group III mGluRs has been poorly characterized; however, all are clearly activated by L-AP4 (10–12, 15). Surprisingly,
the agonist potencies on mGluR7 are very low, being almost 1000 times lower
than those determined on mGluR4 (11, 12). Whether this is because of the
expression of this receptor subtype in heterologous cells or is also true in neurons remains to be elucidated. However, very high concentrations of L-AP4
are required to inhibit AC in some neurons maintained in culture (68). In addition, high concentrations of L-AP4 are required for activation of some mGluR
autoreceptors (see below).
GROUP III mGLURs
STRUCTURE AND FUNCTIONAL DOMAINS
OF CLONED MGLURS
General Structure
As mentioned previously, mGluRs and CaR share no sequence homology
with any other GPCRs. They all possess a surprisingly large N-terminal ex-
METABOTROPIC GLUTAMATE RECEPTORS
215
Figure 4 Schematic representation of an mGluR. The region rich in cysteine residues is indicated
with black circles. The segment in the second intracellular loop that is important for G-protein
coupling specificity in indicated in black.
tracellular domain, seven putative TMDs separated by short intra- and extracellular loops, and a cytoplasmic carboxyl-terminal domain variable in length
(Figure 4). Nineteen cysteine residues located in the predicted extracellular
domain and extracellular loops are conserved in all members of this receptor
family, which suggests important roles for these residues either in the threedimensional structure of the molecule or in the intramolecular transduction.
Accordingly, a high sensitivity of glutamate-stimulated PI turnover to reducing
agents has been reported (69).
The Glutamate Binding Site
Whereas the agonist binding site for small ligands in most GPCRs is located in
a pocket formed by the seven transmembrane domain segments (70), this is not
the case in mGluRs. O’Hara and co-workers (71) noticed a weak sequence similarity of the extracellular domain of mGluRs with bacterial periplasmic binding
proteins (PBP), especially with the leucine, isoleucine, valine binding protein
(LIVBP). This homology was therefore used to construct a model based on
the reported three-dimensional structures of several PBPs. This model predicts
that the extracellular domain of mGluRs is made up of two globular domains
with a hinge region (Figure 4). The glutamate binding site is proposed to be
equivalent to the known amino acid binding sites of PBPs. This model allowed
the identification of two residues, S165 and T188, in the extracellular domain
216
CONN & PIN
of mGluR1, mutation of which affects glutamate affinity (71). This model
is also supported by the construction of chimeric receptors that exchange the
LIVBP-like domain between two mGluRs with different pharmacology (72,
73). It is noteworthy that loss-of-function mutations were identified in close
proximity of the hinge region of the parathyroid CaR in patients who had genetic diseases that affected Ca2+ homeostasis (74, 75). Finally, this model
received indirect confirmation from work on the glutamate receptor channel
subunits. The same computational analysis revealed that these receptor subunits possess two domains homologous to PBP, one homologous to LIVBP, and
one homologous to lysine, arginine, ornithine binding protein (LAOBP) (71).
Recently, an analysis of mutated NMDA-R1 subunit and chimeric α-amino-3hydroxy-5-methyl-isoxazole-4-propionate (AMPA)/kainate receptor subunits
revealed that the LAOPB domain is likely involved in the agonist binding (76,
77). Moreover, production of the LAOBP-like domain of the AMPA receptor
subunit GluR4 as a soluble protein in insect cells revealed that this domain can
bind glutamate and has the same pharmacologic profile as the native subunit
(78). All glutamate receptors may therefore share a similar structure for their
agonist recognition domain.
G-Protein Coupling
The regions involved in the activation of G-proteins by the other GPCRs have
been extensively studied (70, 79). The DRY (or ERW) tripeptide found at the
N-terminal end of the second intracellular loop of most GPCRs has been shown
to play an important role in the coupling to and activation of the G-proteins.
Moreover, cysteine residues located downstream of the seventh TMD are often
palmitoylated and are therefore likely anchored to the plasma membrane (80).
This generates a fourth intracellular loop, which is sometimes necessary for
the correct coupling to G-protein (80). Finally, the third intracellular loop of
most GPCRs plays a critical role in the G-protein coupling specificity. Both its
N- and C-terminal ends are supposed to fold into amphipathic α helices that
extend toward the cytoplasm TM5 and 6, respectively (81). It has recently been
reported that the C-terminal end of the muscarinic receptor directly interacts
with the C-terminal end of the α subunit of the G-protein (82).
In mGluRs, the DRY signature is absent in any intracellular loops, a cysteine
residue has been shown to be palmytoylated in mGluR4 but not in mGluR1a
(83), and the sequence of the third intracellular loop (i3) is conserved in all
members of this receptor family, thereby making it unlikely to play an key
role in G-protein coupling selectivity. By constructing chimeras between the
PLC-coupled mGluR1 and the AC-coupled mGluR3, it has been shown that
the second intracellular loop (i2) of mGluRs plays a critical role in G-protein
coupling specificity (65, 84, 85) (Figure 4) and that, as described for the other
GPCRs, all intracellular segments are indeed involved in the coupling and
METABOTROPIC GLUTAMATE RECEPTORS
217
activation of the G-protein, apparently controling the coupling efficacy (84).
In agreement with the involvement of i3 in G-protein coupling, a mutation in
this loop of the human CaR1 that prevents the receptor from activating PLC has
been found in familial hypocalciuric hypercalcemia patients (74). Interestingly,
i2 of mGluRs likely possesses amphipathic α helices that extend TM3 and 4
toward the cytoplasm (65) and is likely to interact directly with the carboxylterminal end of the G-protein α subunit (85). Taken together, these results
strongly suggest that i2 of mGluRs plays a role equivalent to that of i3 of the
other GPCRs.
The role of the large intracellular C-terminal domain of mGluR1a and
mGluR5a and b is not known. As discussed earlier, this domain likely facilitates
the coupling of the receptor to the G-protein (8, 30, 31, 33). However, this may
not be the main role of these 300 amino acid residues. These residues may be
involved in the specific targeting of these receptors to specific compartments
in neurons (see 86). In addition, the presence of multiple serine and threonine
residues that could constitute the target for GPCR kinases, several putative
protein kinase (including MAP kinase) phosphorylation sites (87), and SH3
binding sites strongly suggests that this domain is involved in the regulation
of the receptor. This will be a direction for intense investigation in the coming
years.
Intramolecular Transduction
As described above, the glutamate binding site is located in the large extracellular domain, and the G-protein coupling region corresponds to the intracellular
loops separating the TMDs. It remains now to understand how the binding of
glutamate in the LIVBP-like domain induces the conformational changes in the
intracellular loops required for the activation of the G-protein.
The mode of action of PBPs has been extensively studied (88). It may
help in proposing different hypotheses for the intramolecular transduction in
mGluRs. PBPs are periplasmic proteins involved in the the high-affinity transport of amino acids, carbohydrates, and ions into the bacterial cytoplasm. As
mentioned above, PBPs are composed of two lobes separted by a hinge region
where the ligand binds. On ligand binding, the two lobes close like a clamshell;
the liganded, closed PBP interacts with a complex of two transmembrane proteins. The ligand is then delivered to the transmembrane proteins that will
carry it into the cytoplasm, thanks to the activity of an associated cytoplasmic
ATPase (88). By analogy with this mode of action of PBPs, and considering
that most ligands interact within a cavity formed by the 7TMD in GPCRs, the
LIVBP-like domain of mGluRs may simply serve to trap glutamate and then
deliver it to another site located in the 7TMD. An alternative hypothesis is that
the big change in conformation in the LIVBP-like domain associated with its
closure will be transduced to the 7TMD thanks to the cysteine-rich region.
218
CONN & PIN
REGULATION OF SECOND MESSENGERS
BY MGLURS IN NATIVE SYSTEMS
Phosphoinositide Hydrolysis as a Transduction
System for mGluRs
mGluRs couple to activation of phosphoinositide hydrolysis in a number of
native preparations, including cultured astrocytes, cultured neurons, synaptoneurosomes, and brain slices (see 89 for review). As would be predicted from
studies in expression systems, evidence suggests that most mGluR-mediated
phosphoinositide hydrolysis responses in brain slices and cultured cells are mediated by group I mGluRs (46, 90–94) but not group II (95) or group III (96)
mGluRs. Evidence suggests, however, that novel mGluRs may also exist that
couple to phosphoinositide hydrolysis. For instance, Chung et al (97, 98) reported evidence for a phosphoinositide hydrolysis–coupled mGluR in cortical
slices that does not correspond to any of the previously cloned mGluR subtypes. This receptor is insensitive to 1S, 3R-ACPD but is selectively activated by
BrHIBO or (R, S)4-methylhomoibotenic acid. Earlier studies that suggested the
existence of multiple mGluR subtypes coupled to activation of phosphoinositide
hydrolysis in native tissues have been discussed in previous reviews (6, 89)
Coupling of mGluRs to Changes in cAMP Accumulation
INHIBITION OF ADENYLYL CYCLASE Consistent with studies in expression systems, a number of studies suggest that activation of group II (59, 68, 99, 100)
and group III (40, 68, 100, 101) mGluRs inhibits forskolin-induced increases
in cAMP accumulation in brain slices and neuronal cultures, whereas group
I mGluRs do not (91). In most studies, however, mGluR-mediated inhibition
of the cAMP response to the adenylyl cyclase activator forskolin has been
measured, rather than responses to agonists of receptors that activate adenylyl
cyclase via coupling to GS . It is therefore not clear whether each of the group II
and group III mGluRs actually couple to inhibition of neurotransmitter-induced
increases in cAMP accumulation in native systems. Indeed, as discussed below, activation of group II mGluRs potentiates, rather than inhibits, increases in
cAMP accumulation induced by receptor agonists in adult hippocampal slices
(102), which suggests that group II mGluRs have the opposite effect when
physiologically relevant agonists are used. In contrast, L-AP4 and L-SOP have
been shown to inhibit agonist-induced increases in cAMP accumulation in
hippocampal slices (99), which suggests that group III mGluRs do couple to
inhibition of GS -activated adenylyl cyclase in this region.
INCREASES IN CYCLIC AMP ACCUMULATION There is little compelling evidence
to suggest the presence of an mGluR that is positively coupled to adenylyl
METABOTROPIC GLUTAMATE RECEPTORS
219
cyclase via GS in native preparations. However, mGluR activation potentiates cAMP responses to agonists of other receptors that couple GS , including
vasoactive intestinal polypeptide, 2-chloroadenosine (2-CA), the β-adrenegic
receptor agonist isoproterenol, and prostaglandin E2 (103, 104). Activation of
mGluRs increases basal cAMP accumulation in hippocampal slices by potentiating cAMP responses to adenosine that is already present in the extracellular
space (104). Interestingly, both group I and group II mGluRs can be involved
in potentiating cAMP responses, and the relative contributions of these different mGluR subtypes depends on the tissue being studied. In adult rat hippocampus, group II mGluR agonists potentiate cAMP responses to agonists of
GS -coupled receptors, whereas agonists of group I and group III mGluRs are
without effect (102). In contrast, agonists of group I and group II mGluRs synergistically potentiate cAMP responses in hippocampus from young animals
(105).
Activation of mGluRs Increases Cyclic GMP Accumulation
Okada (106) reported that mGluR activation increases cGMP levels in cerebellar slices and that this response can be blocked by inhibitors of nitric oxide
(NO) synthase. This suggests that the cGMP response to mGluR activation
depends on formation of NO, which can directly activate guanylyl cyclase. At
present, the mGluR subtype that mediates this increase in cGMP in cerebellum
is unknown, although mGluR1 is a strong candidate. Physiologic studies suggest that mGluR activation may also increase cGMP accumulation in the rat
nucleus tractus solitarius (NTS). In this region, mGluR activation has a number
of physiologic effects that can be mimicked by activators of guanylyl cyclase
(107). These responses are not altered by manipulations that increase or decrease NO levels but can be blocked by a selective inhibitor of heme oxygenase,
an enzyme involved in CO synthesis. In contrast, this heme oxygenase inhibitor
did not block the effects of a cell permeable cGMP analogue. Based on these
findings, it has been proposed that mGluR activation regulates certain aspects
of cell excitability and synaptic transmission in the NTS by a mechanism that
depends on CO-induced activation of guanylyl cyclase.
Interestingly, evidence suggests that activation of a group III mGluR in retinal
ON bipolar cells reduces cGMP accumulation. In these cells, glutamate, or
selective group III mGluR agonists, induces a hyperpolarization that is mediated
by reduction of a cGMP-activated cation current that is tonically active (36,
108). This response is probably mediated by coupling of the mGluR to a
cGMP phosphodiesterase and a subsequent reduction in cGMP levels. In situ
hybridization studies suggest that mGluR6 is a likely candidate for the mGluR
subtype that mediates this response (10, 109), although mGluR8 could also be
involved (15).
220
CONN & PIN
Coactivation of mGluRs and AMPA Receptors Increases
Arachidonic Acid Release
Evidence suggests that activation of mGluRs results in increased phospholipase
A2 (PLA2) activity in cortical neuron–glia cultures (110) and that increases in
arachidonic acid (AA) release in cortical astrocytes (111). This response has
been proposed to play a role in glial-neuronal signaling by inhibiting activity
of astrocytic glutamate transporter proteins. Coactivation of mGluRs and αamino-3-hydroxyl-5-methyl-1-isoxazole-4-propionic acid (AMPA) receptors
also induces a dramatic PLA2-dependent increase in AA release in striatal
neurons (112). At present, the mGluR subtypes that lead to increases in AA
release are not known. However, the increase in AA release in striatal neurons
can be elicited by quisqualate, which suggests the possibility of mediation by
a group I mGluR.
A Novel Metabotropic Receptor Coupled
to Activation of Phospholipase D
Recent studies suggest that a novel metabotropic receptor exists in hippocampal
slices that is coupled to activation of phospholipase D (PLD) (113, 114). Interestingly, the pharmacologic profile of the PLD-coupled receptor is consistent
with its being an mGluR but is not consistent with that of any of the mGluR
subtypes that have been cloned to date (113). Further, L-cysteine-sulfinic acid
(L-CSA) is more efficacious than glutamate at activating this receptor (113),
which suggests that L-CSA may serve as an endogenous agonist of this receptor.
ROLES OF mGLURS IN REGULATING ION CHANNELS
AND CELL EXCITABILITY
Modulation of Potassium Channels and Nonselective
Cation Currents
Activation of mGluRs by stimulation of glutamatergic afferents or exogenous
application of mGluR agonists results in widespread and diverse actions on neuronal excitability by modulation of a variety of voltage-dependent and voltageindependent ion channels. A comprehensive treatment of the regulation of ion
channels by mGluRs is beyond the scope of this review but has previously
been reviewed in detail (115, 116). Potassium channels are among the most
common targets for modulation by mGluRs. For instance, in hippocampal
pyramidal cells, activation of mGluRs results in a reduction in a leak potassium
conductance (Ileak ) (117), the calcium-dependent slow afterhyperpolarization
current (IAHP ) (118, 119), a slow noninactivating voltage-dependent potassium
current termed IM (118), and a slowly inactivating voltage-dependent current
METABOTROPIC GLUTAMATE RECEPTORS
221
termed IK(slow) (120). These combined actions of mGluR activation result in a
dramatic increase in cell excitability. Evidence suggests that group I mGluRs
are the predominant mGluRs involved in increasing excitability of hippocampal
CA1 pyramidal cells (46, 121).
mGluRs can also exert direct excitatory effects on neurons by activation of
nonselective cation currents (122–130). The exact mechanisms involved in generation of the cation currents likely vary in different cell types but can include activation of a Na+ /Ca2+ exchanger (124, 128), activation of a Ca2+ -activated
nonspecific cation (CAN) current (125), and activation of a calcium-independent
nonspecific cation channel (127). Interestingly, the mGluR agonist–induced
cation conductance in CA3 pyramidal cells and dorsolateral septal nucleus
neurons may not be dependent on activation of G-proteins (126, 129), which
raises the exciting possibilty that mGluRs may couple to cation channels by a
GTP-binding protein-independent mechanism. Alternatively, mGluR agonists
may activate a novel ionotropic glutamate receptor that has a binding site more
closely related to that of the mGluRs than to that of other ionotropic glutamate
receptors.
mGluR activation can also exert direct inhibitory effects on neurons. For
instance, mGluR activation induces a hyperpolarization of basolateral amygdala
neurons that is likely mediated by opening of potassium channels (131). This
response can be elicited by RS-4C3HPG, which is an agonist at group II mGluRs
and an antagonist at group I mGluRs and has no effect at group III mGluRs
(52). Further, as discussed above, activation of a group III mGluR induces a
marked hyperpolarization of retinal ON bipolar cells (36, 108).
Modulation of Voltage-Dependent Calcium Channels
A number of studies suggest that mGluR activation can decrease currents
through voltage-dependent calcium channels. mGluR activation reduces L-type,
but not N-type, calcium currents in acutely isolated neurocortical neurons (132).
In addition, it reduces N-type, but not L-type, currents in CA3 pyramidal cells
(133), striatal neurons (134), cultured retinal ganglion neurons (135), and neurons in cortical slices (136). In cultured cortical (137) and cerebellar (138)
neurons, mGluR activation reduces both N- and L-type calcium currents. The
mGluR subtype involved in regulating calcium channels also varies depending on the cell type. Inhibition of N-type calcium currents in cortical neurons is likely mediated by both group I and group II mGluRs, whereas group
III-selective agonists are without effect (136). The pharmacologic profile of
inhibition of N-type calcium currents in cultured granule cells is consistent
with mediation by group II but not group I or III mGluRs (138). In olfactory bulb (139), retinal ganglion (135), and a subpopulation of hippocampal
neurons (133, 137), L-AP4 is effective in inhibiting calcium currents, which
222
CONN & PIN
suggests that group III mGluRs may also modulate calcium currents in some
cell types.
Activation of mGluRs has been reported to increase N-type calcium currents
in retinal ganglion neurons (135) and L-type calcium currents in cerebellar
granule cells (138, 140). In both cell types, the receptor that mediates this
response has a pharmacologic profile consistent with a group I mGluR. Both
mGluR1 and mGluR5 are expressed in cerebellar granule cells (141).
REGULATION OF SYNAPTIC TRANSMISSION
BY mGLURS
mGluRs Serve as Presynaptic Autoreceptors
at Glutamatergic Synapses
One of the most prominent physiologic effects of mGluR agonists that is consistent throughout the CNS is reduction of transmission at glutamatergic synapses.
This effect is typically mediated by presynaptic mGluRs that serve as autoreceptors to reduce glutamate release (see 142 for extensive review).
HETEROGENEITY OF mGLUR AUTORECEPTORS In recent years, it has become
clear that multiple mGluR subtypes, which belong to each of the three major
groups, can serve as autoreceptors. In adult hippocampal area CA1, group I and
group III mGluRs serve as autoreceptors, whereas group II mGluRs do not (143,
144). Pharmacologic and immunocytochemical studies suggest that mGluR5
(144, 145) and mGluR7 (143, 146) are the most likely group I and group III
mGluRs to serve as autoreceptors at this synapse, respectively. Interestingly,
the pharmacology of mGluR autoreceptors in neonatal area CA1 differs from
that in adults (147, 148), which suggests that there may be a developmental
regulation of the mGluR subtypes that serve as autoreceptors in this region.
At the lateral perforant path-dentate gyrus synapse, a group III mGluR that
is pharmacologically different from the group III mGluR at the adult Schaffer
collateral-CA1 synapse serves as an autoreceptor (66, 149–151). There is no
involvement of group I or group II mGluRs as autoreceptors at this synapse. At
the medial perforant path synapse, a group II mGluR serves as an autoreceptor
(151, 152), whereas there is no effect of group I-selective agonists. L-AP4
reduces transmission at the medial perforant path synapse with low potency,
which is consistent with the possibility of a role of mGluR7 (151, 153). Consistent with this, there is heavy localization of mGluR7 immunoreactivity in the
middle third of the molecular layer of the dentate gyrus, where medial perforant
path afferents terminate (146).
Both group II and group III mGluRs serve as autoreceptors at the guinea pig
mossy fiber-CA3 synapse (154) and in the spinal cord (155, 156). At corticostriatal synapses, a group II mGluR serves as an autoreceptor, whereas there
METABOTROPIC GLUTAMATE RECEPTORS
223
is no effect of group III mGluR activation (157). The pharmacologic profiles
of mGluR autoreceptors at other synapses have not been rigorously examined,
although group III mGluR agonists have been shown to reduce transmission
at several other glutamatergic synapses, including synapses in the olfactory
cortex, amygdala, neocortex, and olfactory bulb (see 142 for review).
MULTIPLE MECHANISMS OF REGULATION OF GLUTAMATE RELEASE The mechanisms by which mGluR activation reduces glutamate release from presynaptic
terminals are not known. Reduction of voltage-dependent calcium currents, as
described above, probably provides at least one mechanism by which mGluR
activation can reduce glutamate release. Activation of some mGluRs, however,
may reduce glutamate release by mechanisms that are not dependent on regulation of voltage-dependent calcium channels. For instance, L-AP4 induces
a marked reduction in miniature excitatory postsynaptic current (mEPSC) frequency in hippocampal CA1 pyramidal cells (143). In contrast, the nonselective
calcium channel blocker cadmium abolishes evoked EPSCs in this region but
has no effect on mEPSCs (143). Similar results have been reported within hippocampal area CA3 (158) and in corticostriatal co-cultures (159). These data
suggest that L-AP4 must reduce mEPSC frequency by a mechanism that is independent of modulation of voltage-dependent calcium channels. In contrast,
the group I-selective agonist DHPG reduces transmission in area CA1 but has
no effect on either frequency of amplitude of mEPSCs (143). These data suggest that group I and group III mGluRs reduce EPSCs in area CA1 by different
mechanisms.
Another possible mechanism of mGluR autoreceptor function is activation
of presynaptic potassium currents. Sladeczek et al (160) reported that 1S, 3RACPD reduces transmission at excitatory synapses in visual cortex and found
that this effect was inhibited by the potassium channel blocker 4-aminopyridine
(4-AP), which raises the possibility that mGluR activation reduces EPSCs by a
mechanism involving 4-AP-sensitive channels.
Coactivation of Group II mGluRs and β-Adrenergic Receptors
on Glia Can Reduce Glutamate Release Through a Novel Form
of Glial-Neuronal Communication
Recent studies have revealed a novel mechanism by which mGluR activation can
reduce transmission at glutamatergic synapses. As discussed above, activation
of group II mGluRs in adult hippocampal slices results in a marked potentiation
of the cAMP response to the β-adrenergic receptor agonist isoproterenol (102,
104, 161). Evidence suggests that the large increase in cAMP accumulation
that occurs in response to coactivation of group II mGluRs and β-adrenergic
receptors results in release of cAMP or a cAMP metabolite, such as adenosine, from the cells of synthesis (162). This leads to activation of presynaptic
224
CONN & PIN
A1 adenosine receptors on Schaffer collateral terminals and results in a marked
reduction of transmission at the Schaffer collateral-CA1 synapse. Interestingly,
the synergistic increase in cAMP accumulation that leads to this response occurs
in glia rather than in neurons (161). Thus, group II mGluRs (likely mGluR3)
localized on glia are involved in a novel form of glial-neuronal communication
that could play an important role in regulating excitatory synaptic transmission in the hippocampus during periods in which noradrenergic inputs to the
hippocampus are active.
mGluR Activation Can Lead to an Increase
in Glutamate Release
Under certain conditions, mGluR activation can increase, rather than decrease,
glutamate release. For instance, activation of mGluRs in cortical synaptosomes
in the presence of arachidonic acid results in an increase in 4-aminopyridineinduced glutamate release (163). Further, coapplication of trans-ACPD and
arachidonic acid to hippocampal slices results in a lasting potentiation of
evoked excitatory postsynaptic potentials (EPSPs) at the Schaffer collateralCA1 synapse (164). Thus, the potentiation of glutamate release that occurs
when mGluRs are activated in the presence of arachidonic acid is sufficient to
overcome the autoreceptor-mediated depression of transmission at this synapse.
mGluRs Serve as Presynaptic Heteroceptors
at GABA Synapses
Presynaptic mGluRs have been shown to reduce GABA release and inhibitory
synaptic transmission in several brain regions (60, 143, 165–167). As with the
presynaptic autoreceptors, evidence suggests that members of each major group
of mGluRs can serve as presynaptic heteroceptors on GABAergic terminals.
In addition, group II mGluRs reduce transmission at inhibitory synapses in
the accessory olfactory bulb (60), hippocampal area CA3 in young animals
(167), and thalamus (165), whereas group I mGluRs reduce GABA release
from presynaptic terminals in area CA1 of the hippocampus of adult rats (143).
Both group II and group III mGluRs can serve this role in the thalamus (165).
mGluR-induced Modulation of Ligand-Gated Ion Channels
In addition to regulating glutamate and GABA release, mGluRs can regulate
both excitatory and inhibitory transmission by modulating currents through
glutamate and GABA receptor channels. In contrast to regulation of neurotransmitter release, mGluR-mediated modulation of ligand-gated ion channels
allows selective modulation of specific components of synaptic potentials. For
instance, activation of mGluRs enhances NMDA receptor–mediated responses
without modulating responses to activation of non-NMDA ionotropic glutamate
METABOTROPIC GLUTAMATE RECEPTORS
225
receptors in some neuronal populations (168–171). In hippocampal neurons,
this effect appears to be mediated by a group I mGluR (169).
In spinal cord dorsal horn neurons, mGluR activation potentiates currents
through both NMDA and non-NMDA glutamate receptors (172, 173). In the
NTS, mGluR activation reversibly potentiates AMPA-evoked currents and depresses currents through GABAA receptors (122). Interestingly, mGluR activation reduces NMDA-evoked depolarizations in striatal neurons (174). The
impact of mGluR activation on ligand-gated ion channels is therefore highly
variable in different cell populations and is likely to play unique roles in regulating inhibitory and excitatory synaptic transmission in different brain regions.
POTENTIAL CLINICAL USES OF mGLUR
AGONISTS AND ANTAGONISTS
Because of the ubiquitous distribution of glutamatergic synapses, mGluRs have
the potential to participate in a wide variety of functions of the CNS. In addition, because of the wide diversity and heterogeneous distribution of mGluR
subtypes, the opportunity exists for developing highly selective drugs that affect
a limited number of CNS functions. The mGluRs therefore provide a novel
target for development of therepeutic agents that could have a dramatic impact
on treatment of a wide variety of psychiatric and neurologic disorders. Importantly, drugs acting at mGluRs would have more subtle effects on transmission
at glutamatergic synapses than would iGluR agonists and antagonists and would
probably have fewer side effects.
Treatment of Stroke and Neurodegenerative Disorders
One of the most clear potential beneficial effects of mGluR agonists and antagonists is reduction of excitotoxic neuronal damage that occurs after stroke or
traumatic brain injury or in certain neurodegenerative disorders. For instance,
selective antagonists of mGluR subtypes involved in potentiating responses to
activation of iGluRs (see above) could be effective in reducing excitotoxicity, as
could agonists at mGluR autoreceptors. Further, the tremendous heterogeneity
of mGluR subtypes that serve as autoreceptors at different synapses provides
an opportunity for development of drugs that are highly selective for mGluRs
in specific brain regions that may be affected in different neurodegenerative
disorders. Consistent with a potential neuroprotective effect of mGluR ligands, several studies suggest that agonists of group II and group III mGluRs
can be neuroprotective (175–178), whereas agonists of group I mGluRs are
usually without effect or may potentiate excitotoxicity (100, 178). The specific
roles of different mGluRs in regulating excitotoxicity will likely vary, however,
depending on the model and brain region under study.
226
CONN & PIN
mGluR Ligands as Cognitive Enhancers
mGluRs play in important role in a number of forms of synaptic plasticity,
including induction of hippocampal long-term potentiation (see 179 for review).
They also elicit physiologic effects in the hippocampus that might enhance
cognitive function (see 180 for review). These data have led to the suggestion
that mGluR ligands may be useful as cognitive enhancing agents in patients
who have Alzheimer’s disease and other memory impairments. Studies of the
effects of mGluR ligands on tasks that involve learning and memory in rats are
consistent with this hypothesis (181–183). In addition, agonists of group II
and group III mGluRs protect cultured neurons against apoptosis induced by
β-amyloid peptide (184), and group I agonists increase breakdown of amyloid
precursor protein (185). Agonists of any of these receptor subtypes therefore
have the potential to reduce the progression of Alzheimer’s disease.
mGluRs as Targets for Antiepileptic Agents
Activation of mGluRs in the hippocampus has several effects that could facilitate generation of limbic seizures (see 180 for review). Consistent with this,
microinjection of 1S, 3R-ACPD into the hippocampus (186) or thalamus (187)
results in generalized limbic convulsions in rats, and intracerebroventricular
injection of 1S, 3R-ACPD potentiates NMDA-evoked behavioral convulsions
(188). These effects are primarily mediated by group I mGluRs. Interestingly,
the seizure-evoking effect of the group I–selective agonists, DHPG, could be
attenuated either by mGluR antagonists, or by selective agonists of group II
or group III mGluRs (187). Further, (S)-4C3HPG, an antagonist at group I
mGluRs and agonist at group II mGluRs, has anticonvulsant effects in mice
(189, 190). These data suggest that mGluRs may serve as important new targets for development of novel anticonvulsant agents.
Treatment of Movement Disorders
mGluRs may play an important role in various motor circuits, including those
in the spinal cord, basal ganglia, and cerebellum (see 180 for review). It has
therefore been suggested that mGluR ligands may be useful for treatment of
some movement disorders, such as cerebellar ataxia, amyotropic lateral sclerosis, Huntington’s chorea, and Parkinson’s disease. For instance, intrastriatal
injection of mGluR agonists induces motor activation, manifested as contralateral turning, that is mediated by induction of striatal dopamine release (191).
Injection of 1S, 3R-ACPD into the subthalamic nucleus (STN) also induces contralateral turning (192) and induces a Parkinsonian-like rigidity in rats (193).
Drugs selective for mGluRs involved in striatal or STN activation could be
useful in treatment of Parkinson’s disease.
METABOTROPIC GLUTAMATE RECEPTORS
227
Treatment of Pain
Studies of the effects of mGluR agonists and antagonists on responses of thalamic (92, 194) and spinal cord neurons (195, 196) to noxious and non-noxious
stimuli suggest that mGluRs are preferentially involved in transmitting noxious
sensory information in the thalamus and that mGluRs in the spinal cord may
be involved in induction of long-term enhancement of responses to noxious
stimuli. Selective antagonists for the mGluR subtypes involved in transmitting noxious sensory information could be useful in the treatment of acute and
chronic pain.
Treatment of Hypertension
The mGluR agonist 1S, 3R-ACPD directly depolarizes neurons in the NTS and
virtually abolishes evoked inhibitory postsynaptic potentials (IPSPs) (see 142,
180 for reviews). This would be expected to elicit cardiovascular responses
typical of activation of the baroreceptor reflex. Consistent with this, microinjection of trans-ACPD into the NTS induces a dramatic increase in heart rate
and mean arterial pressure (197). In contrast, activation of mGluRs in raphe
obscurus induces a decrease in arterial blood pressure (198). Thus, antagonists
and agonists of mGluRs involved in regulating cardiovascular function in the
NTS and raphe obscurus, respectively, could provide novel centrally acting
agents for treatment of high blood pressure.
SUMMARY AND CONCLUSIONS
A great deal of progress has been made in isolating and characterizing a family
of mGluRs and in determining the physiologic roles of these receptors in mammalian brain. Because of the fundemental roles of mGluRs in a wide variety of
neuronal circuits, these studies are having a significant impact on several areas
in CNS research. In recent years, a number of mGluR agonists and antagonists
have been developed that are selective for specific mGluR subtypes. These
compounds provide valuable research tools that are advancing our understanding of mGluRs even further and are providing important insights to mGluR
function that are relevant to development of novel treatment strategies for a
large number of neurologic and psychiatric disorders.
ACKNOWLEDGMENTS
The authors thank Dr. F. Acher (CNRS-URA400 Paris, France) and Y. Grau for
constructive discussions and Drs. Schoepp, Pellicciari, and Thomsen for sending manuscripts in press. The work of J.P. Pin is supported by grants from Centre National pour la Recherche Scientifique (CNRS), EEC (BIO2-CT93-0243
228
CONN & PIN
and PL95-0228), the French ministry of Education, Research and Professional
Insertion (ACC-SV5, n◦ 9505077), and the Bayer Company (Wupertal, Germany). The work of P.J. Conn is supported by grants from the National Institutes
of Health (NS-28405, NS-31373, and NS-34876), the Council for Tobacco Research, and Wyeth Ayerst Pharmaceuticals (Princeton, NJ).
Visit the Annual Reviews home page at
http://www.annurev.org.
Literature Cited
1. Hollmann M, Heinemann S. 1994. Cloned
glutamate receptors. Annu. Rev. Neurosci.
17:31–108
2. Sladeczek F, Pin JP, Recasens M, Bockaert J, Weiss S. 1985. Glutamate stimulates inositol phosphate formation in striatal neurones. Nature 317:717–18
3. Sugiyama H, Ito I, Hirono C. 1987. A new
type of glutamate receptor linked to inositol phospholipid metabolism. Nature 325:
531–33
4. Masu M, Tanabe Y, Tsuchida K, Shigemoto R, Nakanishi S. 1991. Sequence and
expression of a metabotropic glutamate
receptor. Nature 349:760–65
5. Houamed KM, Kuijper JL, Gilbert TL,
Haldeman BA, O’Hara PJ, et al. 1991.
Cloning, expression, and gene structure
of a G protein-coupled glutamate receptor from rat brain. Science 252:1318–21
6. Schoepp DD, Bockaert J, Sladeczek F.
1990. Pharmacological and functional
characteristics of metabotropic excitatory
amino acid receptors. Trends Pharmacol.
Sci. 11:508–15
7. Tanabe Y, Masu M, Ishii T, Shigemoto R, Nakanishi S. 1992. A family of
metabotropic glutamate receptors. Neuron 8:169–79
8. Pin J, Waeber C, Prezeau L, Bockaert J,
Heinemann SF. 1992. Alternative splicing
generates metabotropic glutamate receptors inducing different patterns of calcium
release in Xenopus oocytes. Proc. Natl.
Acad. Sci. USA 89:10331–35
9. Abe T, Sugihara H, Nawa H, Shigemoto
R, Mizuno N, et al. 1992. Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phosphate/Ca2+ signal transduction.
J. Biol. Chem. 267:13361–68
10. Nakajima Y, Iwakabe H, Akazawa C,
Nawa H, Shigemoto R, et al. 1993.
Molecular characterization of a novel
11.
12.
13.
14.
15.
16.
17.
retinal metabotropic glutamate receptor
mGluR6 with a high agonist selectivity for L-2-amino-4-phosphonobutyrate.
J. Biol. Chem. 268:11868–73
Okamoto N, Hori S, Akazawa C, Hayashi
Y, Shigemoto R, et al. 1994. Molecular
characterization of a new metabotropic
glutamate receptor mGluR7 coupled to
inhibitory cyclic AMP signal transduction. J. Biol. Chem. 269:1231–36
Saugstad JA, Kinzie JM, Mulvihill ER,
Segerson TP, Westbrook GL. 1994.
Cloning and expression of a new member
of the L-2-amino- 4-phosphonobutyric
acid-sensitive class of metabotropic
glutamate receptors. Mol. Pharmacol.
45:367–72
Joly C, Gomeza J, Brabet I, Curry K,
Bockaert J, et al. 1995. Molecular, functional, and pharmacological characterization of the metabotropic glutamate receptor type 5 splice variants: comparison
with mGluR1. J. Neurosci. 15:3970–81
Minakami R, Katsuki F, Yamamoto T,
Nakamura K, Sugiyama H. 1994. Molecular cloning and the functional expression
of two isoforms of human metabotropic
glutamate receptor subtype 5. Biochem.
Biophys. Res. Commun. 199:1136–43
Duvoisin RM, Zhang C, Ramonell K.
1995. A novel metabotropic glutamate receptor expressed in the retina and olfactory bulb. J. Neurosci. 15:3075–83
Iversen L, Mulvihill E, Haldeman B,
Diemer NH, Kaiser F, et al. 1994.
Changes in metabotropic glutamate receptor mRNA levels following global ischemia: increase of a putative presynaptic
subtype (mGluR4) in highly vulnerable
rat brain areas. J. Neurochem. 63:625–33
Laurie DJ, Boddeke HWGM, Hiltscher
R, Sommer B. 1996. HmGlu1d , a novel
splice variant of the human type I
metabotropic glutamate receptor. Eur. J.
Pharmacol. 296:R1–R3
METABOTROPIC GLUTAMATE RECEPTORS
18. Desai MA, Burnett JP, Mayne NG,
Schoepp DD. 1995. Cloning and expression of a human metabotropic glutamate
receptor 1α: enhanced coupling on cotransfection with a glutamate transporter.
Mol. Pharmacol. 48:648–57
19. Flor PJ, Lindauer K, Püttner I, Rüegg
D, Lukic S, et al. 1995. Molecular
cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor
type 2. Eur. J. Neurosci. 7:622–29
20. Emile L, Mercken L, Apiou F, Pradier
L, Bock M-D, et al. 1996. Molecular cloning, functional expression, pharmacological characterization and chromosomal localisation of the human
metabotropic glutamate receptor type 3.
Neuropharmacology. In press
21. Flor PJ, Lukic S, Rüegg D, Leonhardt
T, Knöpfel T, et al. 1995. Molecular cloning, functional expression and
pharmacological characterization of the
human metabotropic glutamate receptor
type 4. Neuropharmacology. 34:149–55
22. Daggett LP, Sacaan AI, Akong M, Rao
SP, Hess SD, et al. 1995. Molecular and
functional characterization of recombinant human metabotropic glutamate receptor subtype 5. Neuropharmacology.
34:871–86
22a. Parmentier M-L, Pin J-P, Bockaert J, Grau
Y. 1996. Cloning and functional expression of a Drosophila metabotropic glutamate receptor expressed in the embryonic
central nervous system. J. Neurosci. In
press
23. Nakanishi S. 1992. Molecular diversity of
glutamate receptors and implications for
brain function. Science 258:597–603
24. Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, et al. 1993. Cloning
and characterization of an extracellular Ca2+ -sensing receptor from bovine
parathyroid. Nature 366:575–80
25. Garrett JE, Capuano IV, Hammerland LG,
Hung BCB, Brown EM, et al. 1995.
Molecular cloning and functional expression of human parathyroid calcium receptor cDNAs. J. Biol. Chem. 270:12919–25
26. Ruat M, Molliver ME, Snowman AM,
Snyder SH. 1995. Calcium sensing receptor: molecular cloning in rat and localization to nerve terminals. Proc. Natl. Acad.
Sci. USA 92:3161–65
27. Riccardi D, Park J, Lee W-S, Gamba G,
Brown EM, et al. 1995. Cloning and functional expression of a rat kidney extracellular calcium/polyvalent cation-sensing
receptor. Proc. Natl. Acad. Sci. USA.
92:131–35
229
28. Ikeda SR, Lovinger DM, McCool BA,
Lewis DL. 1995. Heterologous expression of metabotropic glutamate receptors in adult rat sympathetic neurons:
subtype-specific coupling to ion channels.
Neuron 14:1029–38
29. Aramori I, Nakanishi S. 1992. Signal
transduction and pharmacological characteristics of a metabotropic glutamate
receptor, mGluR1, in transfected CHO
cells. Neuron 8:757–65
30. Pickering DS, Thomsen C, Suzdak PD,
Fletcher EJ, Robitaille R, et al. 1993. A
comparison of two alternatively spliced
forms of a metabotropic glutamate receptor coupled to phosphoinositide turnover.
J. Neurochem. 61:85–92
31. Gabellini N, Manev RM, Candeo P,
Favaron M, Manev H. 1993. Carboxyl domain of glutamate receptor directs its coupling to metabolic pathways. NeuroReport 4:531–34
32. Pin J-P, Duvoisin R. 1995. The metabotropic glutamate receptors: structure and
functions. Neuropharmacology. 34:1–26
33. Prézeau L, Gomeza J, Ahern S, Mary
S, Galvez T, et al. 1996. Changes
in the carboxyl-terminal domain of
metabotropic glutamate receptor 1 by
alternative splicing generate receptors
with differing agonist-independent activity. Mol. Pharmacol. 49:422–29
34. Tanabe Y, Nomura A, Masu M, Shigemotor R, Mizuno N, et al. 1993. Signal transduction, pharmacological properties, and expression patterns of two
rat metabotropic glutamate receptors,
mGluR3 and mGluR4. J. Neurosci.
13:1372–78
35. McCool BA, Pin JP, Brust PF, Harpold
MM, Lovinger DM. 1996. Heterologous
expression of rat group II metabotropic
glutamate receptors (mGluR 2 and 3) in
HEK 293 cells: functional coupling to
a stably expressed ω-conotoxin GVIAsensitive calcium channel. Mol. Pharmacol. 50:912–22
36. Shiells RA, Falk G. 1992. The glutamatereceptor linked cGMP cascade of retinal
on-bipolar cells is pertussis and cholera
toxin-sensitive. Proc. R. Soc. London B
247:17–20
37. Saugstad JA, Segerson TP, Westbrook
GL. 1995. L-AP4-sensitive metabotropic
glutamate receptors activate the G-protein-coupled inwardly rectifying potassium channel in Xenopus oocytes. Soc.
Neurosci. Abstr. 21:843
38. Roberts PJ. 1995. Pharmacological tools
for the investigation of metabotropic
glutamate receptors (mGluRs): phenyl-
230
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
CONN & PIN
glycine derivatives and other selective
antagonists—an update. Neuropharmacology 34:813–19
Ishida M, Saitoh T, Tsuji K, Nakamura
Y, Kataoka K, et al. 1995. Novel agonists for metabotropic glutamate receptors: trans- and cis-2-(2-carboxy-3-methoxymethylcyclopropyl)glycine (transand cis-MCG-I). Neuropharmacology
34:821–27
Bedingfield JS, Kemp MC, Jane DE,
Tse HW, Roberts PJ, et al. 1995.
Structure-activity relationships for a series of phenylglycine derivatives acting at metabotropic glutamate receptors
(mGluRs). Br. J. Pharmacol. 116:3323–
29
Ito I, Kohda A, Tanabe S, Hirose
E, Hayashi E, et al. 1992. 3, 5-dihydroxyphenylglycine: a potent agonist of metabotropic glutamate receptors. NeuroReport 3:1013–16
Favaron M, Manev RM, Candeo P, Arban R, Gabellini N, et al. 1993. Transazetidine-2, 4-dicarboxylic acid activates
neuronal metabotropic receptors. NeuroReport 4:967–70
Brabet I, Mary S, Bockaert J, Pin JP.
1995. Phenylglycine derivatives discriminate between mGluR1- and mGluR5mediated responses. Neuropharmacology
34:895–903
Gomeza J, Mary S, Brabet I, Parmentier M-L, Restituito S, et al. 1996. Coupling of metabotropic glutamate receptors
2 and 4 to Gαl5, Gαl6 and chimeric Gαq/i
proteins: characterization of new antagonists. Mol. Pharmacol. 50:923–30
Manahan-Vaughan D, Reiser M, Pin J-P,
Wilsch V, Bockaert J, et al. 1996. Longterm potentiation in rat dentate gyrus in
vivo: a role for class I metabotropic glutamate receptor subtypes. Neuroscience
72:999–1008
Gereau RW, Conn PJ. 1995. Roles of
specific metabotropic glutamate receptor
subtypes in regulation of hippocampal
CA1 pyramidal cell excitability. J. Neurophysiol 74:122–29
Knöpfel T, Sakaki J, Flor PJ, Baumann
P, Sacaan AI, et al. 1995. Profiling of
trans-azetidine-2, 4-dicarboxylic acid at
the human metabotropic glutamate receptors mGlu1b,−2,−4a and −5a . Eur. J.
Pharmacol. Mol. Pharmacol. 288:389–
92
Hayashi Y, Tanabe Y, Aramori I, Masu
M, Shimamoto K. 1992. Agonist analysis of 2-(carboxycyclopropyl)glycine isomers for cloned metabotropic glutamate
receptor subtypes expressed in Chinese
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
hamster ovary cells. Br. J. Pharmacol.
107:539–43
Thomsen C, Mulvihill ER, Haldeman B,
Pickering DS, Hampson DR, et al. 1993.
A pharmacological characterization of the
mGluR1α subtype of the metabotropic
glutamate receptor expressed in a cloned
baby hamster kidney cell line. Brain Res.
619:22–28
Thomsen C, Boel E, Suzdak PD. 1994.
Actions of phenylglycine analogs at subtypes of the metabotropic glutamate receptor family. Eur. J. Pharmacol. Mol.
Pharmacol. 267:77–84
Ferraguti F, Cavanni P, Eistetter H, Salvagno C, Ratti E, et al. 1994. Competitive
antagonism by phenylglycine derivatives
at type 1 metabotropic glutamate receptor.
Mol. Cell. Neurosci. 5:269–76
Hayashi Y, Sekiyama N, Nakanishi S,
Jane DE, Sunter DC, et al. 1994. Analysis of agonist and antagonist activities
of phenylglycine derivatives for different
cloned metabotropic glutamate receptor
subtypes. J. Neurosci. 14:3370–77
Pellicciari R, Luneia R, Costantino G,
Marinozzi M, Natalini B, et al. 1995.
1-aminoindan-1, 5-dicarboxylic acid: a
novel antagonist at phospholipase Clinked metabotropic glutamate receptors.
J. Med. Chem. 38:3717–19
Annoura H, Fukunaga A, Uesugi M,
Tatsuoka T, Horikawa Y. 1996. A novel
class of antagonists for metabotropic
glutamate receptors, 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylates.
Bioorg. Med. Chem. Lett. 6:763–66
Thomsen C, Bau A, Faarup P, Foged C,
Kanstrup A, et al. 1994. Effects of bromohomoibotenate on metabotropic glutamate receptors. NeuroReport 5:2417–
20
Tellier F, Acher F, Brabet I, Pin J-P,
Bockaert J, et al. 1995. Synthesis of
conformationally-constrained stereospecific analogs of glutamic acid as antagonists of metabotropic receptors. Bioorg.
Med. Chem. Lett. 5:2627–32
Flor PJ, Gomeza J, Tones MA, Kuhn R,
Pin JP, et al. 1996. The C-terminal domain
of the mGluR1 metabotropic glutamate
receptor affects sensitivity to agonists. J.
Neurochem. 67:58–63
Kingston AE, Burnett JP, Mayne NG,
Lodge D. 1995. Pharmacological analysis of 4-carboxyphenylglycine derivatives: comparison of effects on mGluR1
α and mGluR5a subtypes. Neuropharmacology 34:887–94
Schoepp DD, Johnson BG, Salhoff CR,
Valli MJ, Desai MA, et al. 1995. Selective
METABOTROPIC GLUTAMATE RECEPTORS
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
inhibition of forskolin-stimulated cyclic
AMP formation in rat hippocampus
by a novel mGluR agonist, 2R, 4R4-aminopyrolidine-2, 4-dicarboxylate.
Neuropharmacology 34:843–50
Hayashi Y, Momiyama A, Takahashi T,
Ohishi H, Ogawa-Meguro R, et al. 1993.
Role of a metabotropic glutamate receptor
in synaptic modulation in the accessory
olfactory bulb. Nature 366:687–90
Desai MA, Smith TS, Conn PJ. 1992.
Multiple metabotropic glutamate receptors regulate hippocampal function.
Synapse 12:206–13
Cavanni P, Pinnola V, Mugnaini M,
Trist D, Van Amsterdam FTM, et al.
1994. Pharmacological analysis of carboxyphenylglycines at metabotropic glutamate receptors. Eur. J. Pharmacol. Mol.
Pharmacol. 269:9–15
Thomsen C, Bruno V, Nicoletti F,
Marinozzi M, Pellicciari R. 1996. (2S,
1′ S, 2′ S, 3′ R)-2-(2′ carboxy-3′ -phenylcyclopropyl)glycine, a potent and selective
antagonist of type 2 metabotropic glutamate receptors. Mol. Pharmacol. 50:6–9
Wermuth CG, Mann A, Schoenfelder A,
Wright RA, Johnson BG, et al. 1996.
(2S, 4S)-2-amino-4-(4, 4-diphenylbut-1yl)-pentane-1, 5-dioic acid: a potent
and selective antagonist for metabotropic
glutamate receptors negatively linked to
adenylate cyclase. J. Med. Chem. 39:814–
16
Pin J-P, Joly C, Heinemann SF, Bockaert
J. 1994. Domains involved in the specificity of G protein activation in phospholipase C-coupled metabotropic glutamate
receptors. EMBO J. 13:342–48
Johansen PA, Chase LA, Sinor AD, Koerner JF, Johnson RL, et al. 1995. Type 4a
metabotropic glutamate receptor: identification of new potent agonists and differentiation from the L-(+)-2-amino-4phosphonobutanoic acid-sensitive receptor in the lateral perforant pathway in rats.
Mol. Pharmacol. 48:140–49
Johansen PA, Robinson MB. 1995.
Identification of 2-amino-2-methyl-4phosphonobutanoic acid as an antagonist
at the mGlu4a receptor. Eur. J. Pharmacol.
Mol. Pharmacol. 290:R1–R3
Prézeau L, Carrette J, Helpap B, Curry
K, Pin JP, et al. 1994. Pharmacological
characterization of metabotropic glutamate receptors in several types of brain
cells in primary cultures. Mol. Pharmacol. 45:570–77
Vignes M, Guiramand J, Sassetti I, Recasens M. 1993. Effect of thiol reagents
on phosphoinositide hydrolysis in rat
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
231
brain synaptoneurosomes. Eur. J. Neurosci. 5:327–34
Savarese TM, Fraser CM. 1992. In vitro
mutagenesis and the search for structurefunction relationships among G proteincoupled receptors. Biochem. J. 283:1–19
O’Hara PJ, Sheppard PO, Thogersen H,
Venezia D, Haldeman BA, et al. 1993. The
ligand-binding domain in metabotropic
glutamate receptors is related to bacterial periplasmic binding proteins. Neuron
11:41–52
Takahashi K, Tsuchida K, Tanabe Y,
Masu M, Nakanishi S. 1993. Role
of the large extracellular domain of
metabotropic glutamate receptors in agonist selectivity determination. J. Biol.
Chem. 268:19341–45
Tones MA, Bendali H, Flor PJ, Knöpfel
T, Kuhn R. 1995. The agonist selectivity
of a class III metabotropic glutamate receptor, human mGluR4a, is determined
by the N-terminal extracellular domain.
NeuroReport 7:117–20
Pollak MR, Brown EM, Chou Y-HW,
Hebert SC, Marx S, et al. 1993. Mutations in the human Ca2+ -sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75:1297–1303
Pollak MR, Brown EM, Estep HL,
McLaine PN, Kifor O, et al. 1994. Autosomal dominant hypocalcaemia caused
by a Ca2+ -sensing receptor gene mutation. Nat. Genet. 8:303–07
Stern-Bach Y, Bettler B, Hartley M, Sheppard PO, O’Hara PJ, et al. 1994. Agonist
selectivity of glutamate receptors is specified by two domains structurally related
to bacterial amino acid-binding proteins.
Neuron 13:1345–57
Kuryatov A, Laube B, Betz H, Kuhse J.
1994. Mutational analysis of the glycinebinding site of the NMDA receptor: structural similarity with bacterial amino acidbinding proteins. Neuron 12:1291–1300
Kuusinen A, Arvola M, Keinanen K.
1995. Molecular dissection of the agonist
binding site of an AMPA receptor. EMBO
J. 14:6327–32
Ostrowski J, Kjelsberg MA, Caron MG,
Lefkowitz RJ. 1992. Mutagenesis of the
β2-adrenergic receptor: how structure
elucidates function. Annu. Rev. Pharmacol. Toxicol. 32:167–83
Bouvier M, Chidiac P, Hebert TE, Loisel
TP, Moffett S, et al. 1995. Dynamic
palmitoylation of G-protein-coupled receptors in eucaryotic cells. Meth. Enzymol. 250:300–14
232
CONN & PIN
81. Bluml K, Mutschler E, Wess J. 1994. Insertion mutagenesis as a tool to predict
the secondary structure of a muscarinic
receptor domain determining specificity
of G-protein coupling. Proc. Natl. Acad.
Sci. USA 91:7980–84
82. Liu J, Conklin BR, Blin N, Yun J, Wess
J. 1995. Identification of a receptor Gprotein contact site critical for signaling
specificity and G-protein activation. Proc.
Natl. Acad. Sci. USA 92:11642–46
83. Alaluf S, Mulvihill ER, McIlhinney RAJ.
1995. The metabotropic glutamate receptor mGluR4, but not mGluR1 α, is palmitoylated when expressed in BHK cells. J.
Neurochem. 64:1548–55
84. Gomeza J, Joly C, Kuhn R, Knöpfel T,
Bockaert J, et al. 1996. The second intracellular loop of metabotropic glutamate
receptor 1 cooperates with the other intracellular domains to control coupling
to G-proteins. J. Biol. Chem. 271:2199–
205
85. Pin J-P, Gomeza J, Prézeau L, Joly C,
Bockaert J. 1996. The metabotropic glutamate receptors: differences and similarities with the other G-protein coupled receptors. In Alfred Benzon Symposium 39—Structure and Function of
7TM Receptors, ed. TW Schwartz, SA
Hjorth, J Sandholm Kastruped, pp. 343–
56. Copenhagen: Munksgaard.
86. Pin J-P, Bockaert J. 1995. Get receptive to
metabotropic glutamate receptors. Curr.
Opin. Neurobiol. 5:342–49
87. Alaluf S, Mulvihill ER, McIlhinney RAJ.
1995. Rapid agonist mediated phosphorylation of the metabotropic glutamate receptor 1α by protein kinase C in permanently transfected BHK cells. FEBS Lett.
367:301–05
88. Quiocho FA. 1990. Atomic structures
of periplasmic binding proteins and the
high-affinity active transport systems in
bacteria. Philos. Trans. R. Soc. London B
326:341–51
89. Conn PJ, Chung D, Winder DG, Gereau
RW, Boss V. 1995. Biochemical transduction systems operated by excitatory amino
acids. In CNS Neurotransmitters and Neuromodulators, ed. TW Stoneed. pp. 181–
200. New York: CRC Press
90. Schoepp DD, Conn PJ. 1993. Metabotropic glutamate receptors in brain function
and pathology. Trends Pharmacol. Sci.
14:13–20
91. Schoepp DD, Goldsworthy J, Johnson
BG, Salhoff CR, Baker SR. 1994. 3, 5dihydroxyphenylglycine is a highly selective agonist for phosphoinositide-linked
metabotropic glutamate receptors in the
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
rat hippocampus. J. Neurochem. 63:769–
72
Eaton SA, Jane DE, Jones PLSJ, Porter RHP, Pook PC-K, et al. 1993. Competitive antagonism at metabotropic glutamate receptors by (S)-4-carboxyphenylglycine and (RS)-α methyl-4-carboxyphenylglycine. Eur. J. Pharmacol.
244:195–97
Miller S, Romano C, Cotman CW.
1995. Growth factor upregulation of
a phosphoinositide-coupled metabotropic
glutamate receptor in cortical astrocytes.
J. Neurosci. 15:6103–9
Toms NJ, Jane DE, Tse HW, Roberts PJ.
1995. Characterization of metabotropic
glutamate receptor–stimulated phosphoinositide hydrolysis in rat cultured cerebellar granule cells. Br. J. Pharmacol.
116:2824–27
Nicoletti F, Casabona G, Genazzani
AA, L’Episcopo MR, Shinozaki H.
1993. 2s , 1′R , 2′R , 3′R )-2(2, 3-Dicarboxycyclopropyl) glycine enhances quisqualate-stimulated inositol phospholipid
hydrolysis in hippocampal slices. Eur. J.
Pharmacol. 245:297–98
Desai MA, Conn PJ. 1990. Selective activation of phosphoinositide hydrolysis by
a rigid analogue of glutamate. Neurosci.
Lett. 109:157–62
Chung DS, Winder DG, Conn PJ.
1994. 4-bromohomoibotenic acid selectively activates a 1-aminocyclopentane1S, 3R-dicarboxylic acid-insensitive
metabotropic glutamate receptor coupled
to phosphoinositide hydrolysis in rat
cortical slices. J. Neurochem. 63:133–39
Chung DS, Conn PJ. 1996.Characterization of an ACPD-insensitive mGluR coupled to phosphoinositide hydrolysis. Neuropharmacology. In press. Abstr.
Wright RA, Schoepp DD. 1996. Differentiation of group 2 and group 3 metabotropic glutamate receptor cAMP responses in the rat hippocampus. Eur. J.
Pharmacol. 297:275–82
Bruno V, Battaglia G, Copani A, Giffard
RG, Raciti G, et al. 1995. Activation of
class II or III metabotropic glutamate receptors protects cultured cortical neurons
against excitotoxic degeneration. Eur. J.
Neurosci. 7:1906–13
Schoepp DD, Johnson BG, Salhoff CR,
Wright RA, Goldsworthy JS, et al. 1995.
Second-messenger responses in brain
slices to elucidate novel glutamate receptors. J. Neurosci. Methods 59:105–10
Winder DG, Conn PJ. 1995. Metabotropic
glutamate receptor (mGluR)-mediated
METABOTROPIC GLUTAMATE RECEPTORS
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
potentiation of cyclic AMP responses
does not require phosphoinositide hydrolysis: mediation by a group II–like
mGluR. J. Neurochem. 64:592–99
Alexander SPH, Curtis AR, Hill SJ, Kendall DA. 1992. Activation of a metabotropic excitatory amino acid receptor potentiates A2b adenosine receptorstimulated cyclic AMP accumulation.
Neurosci. Lett. 146:231–33
Winder DG, Conn PJ. 1993. Activation of metabotropic glutamate receptors increases cAMP accumulation in
hippocampus by potentiating responses
to endogenous adenosine. J. Neurosci.
13:38–44
Schoepp DD, Johnson BG, Monn JA.
1996. (1S, 3R)-1-Aminocyclopentane-1,
3-dicarboxylic acid-induced increases in
cAMP formation in the neonatal rat hippocampus are mediated by a synergistic
interaction between phosphoinositide and
inhibitory cyclic AMP-coupled mGluRs.
J. Neurochem. 66:1981–85
Okada D. 1992. Two pathways of
cyclic GMP production through glutamate receptor–mediated nitric oxide synthesis. J. Neurochem. 59:1203–10
Glaum SR, Miller RJ. 1993. Zinc
protoporphyrin-1X blocks the effects of
metabotropic glutamate receptor activation in the rat nucleus tractus solitarius.
Mol. Pharmacol. 43:965–69
Thoreson WB, Miller RF. 1994. Actions
of (1S, 3R)-1-aminocyclopentane-1, 3dicarboxylic acid (1S, 3R-ACPD) in retinal ON bipolar cells indicate that it is an
agonist at L-AP4 receptors. J. Gen. Physiol. 103:1019–34
Hartveit E, Brandstätter JH, Enz R,
Wässle H. 1995. Expression of the mRNA
of seven metabotropic glutamate receptors (mGluR1 to 7) in the rat retina. An
in situ hybridization study on tissue sections and isolated cells. Eur. J. Neurosci.
7:1472–83
Kim DK, Rordorf G, Nemenoff RA, Koroshetz WJ, Bonventre JV. 1995. Glutamate stably enhances the activity of
two cytosolic forms of phospholipase A2
in brain cortical cultures. Biochem. J.
310:83–90
Stella N, Tencé M, Glowinski J, Prémont
J. 1994. Glutamate-evoked release of
arachidonic acid from mouse brain astrocytes. J. Neurosci. 14:568–75
Dumuis A, Sebben M, Fagni L, Prezeau
L, Manzoni O, et al. 1993. Stimulation by
glutamate receptors of arachidonic acid
release depends on the Na+ /Ca2+ ex-
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
233
changer in neuronal cells. Mol. Pharmacol. 43:976–81
Boss V, Nutt KM, Conn PJ. 1994. Lcysteine sulfinic acid as an endogenous
agonist of a novel metabotropic receptor
coupled to stimulation of phospholipase
D activity. Mol. Pharmacol. 45:1177–82
Holler T, Cappel E, Klein J, Loffelholz K.
1993. Glutamate activates phospholipase
D in hippocampal slices of newborn and
adult rats. J. Neurochem. 61:1569–72
Gerber U, Gähwiler BH. 1994. Modulation of ionic currents by metabotropic
glutamate receptors. In The Metabotropic
Glutamate Receptors, ed. PJ Conn,
J Patel, pp. 125–46. Totowa, NJ: Humana.
Westbrook GL, Sahara Y, Saugstad JA,
Kinzie JM, Segerson TP. 1993. Regulation of ion channels by ACPD and AP4.
Funct. Neurol. 8:56
Guérineau NC, Gähwiler BH, Gerber U.
1994. Reduction of resting K+ current by
metabotropic glutamate and muscarinic
receptors in rat CA3 cells: mediation by
G-proteins. J. Physiol. 474:27–33
Charpak S, Gähwiler BH, Do KQ,
Knopfel T. 1990. Potassium conductances
in hippocampal neurons blocked by excitatory amino-acid transmitters. Nature
347:765–67
Desai MA, Conn PJ. 1991. Excitatory effects of ACPD receptor activation in the
hippocampus are mediated by direct effects on pyramidal cells and blockade
of synaptic inhibition. J. Neurophysiol.
66:40–52
Lüthi A, Gähwiler BH, Gerber U. 1996.
A slowly inactivating potassium current
in CA3 pyramidal cells of rat hippocampus in vitro. J. Neurosci. 16:586–94
Davies CH, Clarke VRJ, Jane DE,
Collingridge GL. 1995. Pharmacology of
postsynaptic metabotropic glutamate receptors in rat hippocampal CA1 pyramidal neurons. Br. J. Pharmacol. 116:1859–
69
Glaum SR, Miller RJ. 1992. Metabotropic
glutamate receptors mediate excitatory
transmission in the nucleus of the solitary
tract. J. Neurosci. 12:2251–58
Staub C, Vranesic I, Knopfel T. 1992. Responses to metabotropic glutamate receptor activation in cerebellar Purkinje cells:
induction of an inward current. Eur. J.
Neurosci. 4:832–39
Linden DJ, Smeyne M, Connor JA. 1994.
Trans-ACPD, a metabotropic receptor agonist, produces calcium mobilization and
an inward current in cultured cerebellar Purkinje neurons. J. Neurophysiol.
71:1992–98
234
CONN & PIN
125. Crépel V, Aniksztejn L, Ben-Ari Y, Hammond C. 1994. Glutamate metabotropic
receptors increase a Ca2+ -activated nonspecific cationic current in CA1 hippocampal neurons. J. Neurophysiol.
72:1561–69
126. Guérineau NC, Bossu J-L, Gähwiler
BH, Gerber U. 1995. Activation of
a nonselective cationic conductance by
metabotropic glutamatergic and muscarinic agonists in CA3 pyramidal neurons of the rat hippocampus. J. Neurosci.
15:4395–407
127. Pozzo Miller LD, Petrozzino JJ, Connor JA. 1995. G protein-coupled receptors mediate a fast excitatory postsynaptic
current in CA3 pyramidal neurons in hippocampal slices. J. Neurosci. 15:8320–30
128. McBain CJ, DiChiara TJ, Kauer JA. 1994.
Activation of metabotropic glutamate receptors differentially affects two classes
of hippocampal interneurons and potentiates excitatory synaptic transmission. J.
Neurosci. 14:4433–45
129. Zheng F, Hasuo H, Gallagher JP. 1995.
1S, 3R-ACPD-preferring inward current
in rat dorsolateral septal neurons is mediated by a novel excitatory amino acid
receptor. Neuropharmacology 34:905–17
130. Mercuri NB, Stratta F, Calabresi P, Bonci
A, Bernardi G. 1993. Activation of
metabotropic glutamate receptors induces
an inward current in rat dopamine mesencephalic neurons. Neuroscience 56:399–
407
131. Rainnie DG, Holmes KH, ShinnickGallagher P. 1994. Activation of postsynaptic metabotropic glutamate receptors
by trans-ACPD hyperpolarizes neurons
of the basolateral amygdala. J. Neurosci.
14:7208–20
132. Sayer RJ, Schwindt PC, Crill WE.
1992. Metabotropic glutamate receptormediated suppression of L-type calcium
current in acutely isolated neorcortical
neurons. J. Neurophysiol. 68:833–42
133. Swartz KJ, Bean BP. 1992. Inhibition of
calcium channels in rat CA3 pyramidal
neurons by a metabotropic glutamate receptor. J. Neurosci. 12:4358–71
134. Stefani A, Pisani A, Mercuri NB,
Bernardi G, Calabresi P. 1994. Activation of metabotropic glutamate receptors inhibits calcium currents and GABAmediated synaptic potentials in striatal
neurons. J. Neurosci. 14:6734–43
135. Rothe T, Bigl V, Grantyn R. 1994.
Potentiating and depressant effects of
metabotropic glutamate receptor agonists
on high-voltage-activated calcium cur-
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
rents in cultured retinal ganglion neurons from postnatal mice. Pflugers Arch.
426:161–70
Choi S, Lovinger DM. 1996. Metabotropic glutamate receptor modulation
of voltage-gated Ca2+ channels involves
multiple receptor subtypes in cortical neurons. J. Neurosci. 16:36–45
Sahara Y, Westbrook GL. 1993. Modulation of calcium currents by a metabotropic
glutamate receptor involves fast and
slow kinetic components in cultured hippocampal neurons. J. Neurosci. 13:3041–
50
Chavis P, Fagni L, Bockaert J, Lansman
JB. 1995. Modulation of calcium channels by metabotropic glutamate receptors
in cerebellar granule cells. Neuropharmacology 34:929–37
Trombley PQ, Westbrook GL. 1992. LAP4 inhibits calcium currents and synaptic transmission via a G–protein-coupled
glutamate receptor. J. Neurosci. 12:2043–
50
Chavis P, Nooney JM, Bockaert J, Fagni
L, Feltz A, et al. 1995. Facilitatory coupling between a glutamate metabotropic
receptor and dihydropyridine-sensitive
calcium channels in cultured cerebellar
granule cells. J. Neurosci. 15:135–43
Testa CM, Catania MV, Young AB. 1994.
Anatomical distribution of metabotropic
glutamate receptors in mammalian brain.
In The Metabotropic Glutamate Receptors, ed. PJ Conn, J Pateled, pp. 99–124.
Totowa, NJ: Humana
Glaum SR, Miller RJ. 1994. Acute
regulation of synaptic transmission by
metabotropic glutamate receptors. In The
Metabotropic Glutamate Receptors, ed.
PJ Conn, J Patel, pp. 147–72. Totowa, NJ:
Humana
Gereau RW, Conn PJ. 1995. Multiple
presynaptic metabotropic glutamate receptors modulate excitatory and inhibitory synaptic transmission in hippocampal area CA1. J. Neurosci. 15:6879–89
Manzoni O, Bockaert J. 1995. Metabotropic glutamate receptors inhibiting excitatory synapses in the CA1 area of rat
hippocampus. Eur. J. Neurosci. 7:2518–
23
Romano C, Sesma MA, McDonald CT,
O’Malley K, Van den Pol AN, et al. 1995.
Distribution of metabotropic glutamate
receptor mGluR5 immunoreactivity in rat
brain. J. Comp. Neurol. 355:455–69
Bradley SR, Levey AI, Hersch SM, Conn
PJ. 1996. Immunocytochemical localization of group III metabotropic gluta-
METABOTROPIC GLUTAMATE RECEPTORS
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
mate receptors in the hippocampus with
subtype-specific antibodies. J. Neurosci.
16:2044–56
Baskys A, Malenka RC. 1991. Agonists at
metabotropic glutamate receptors presynaptically inhibit EPSCs in neuronal rat
hippocampus. J. Physiol. 444:687–701
Vignes M, Clarke VRJ, Davies CH,
Chambers A, Jane DE, et al. 1995. Pharmacological evidence for an involvement
of group II and group III mGluRs in
the presynaptic regulation of excitatory
synaptic responses in the CA1 region of
rat hippocampal slices. Neuropharmacology 34:973–82
Koerner JF, Cotman CW. 1981. Micromolar L-2-amino-4-phosphonobutyric
acid selectively inhibits perforant path
synapses from lateral entorhinal cortex.
Brain Res. 216:192–98
Bushell TJ, Jane DE, Tse H-W, Watkins
JC, Davies CH, et al. 1995. Antagonism of
the synaptic depressant actions of L-AP4
in the lateral perforant path by MAP4.
Neuropharmacology 34:239–41
Macek TA, Winder DG, Gereau RW, IV,
Ladd CO, Conn PJ. 1996. Differential
involvement of group II and group III
mGluRs asautoreceptors at lateral and
medial perforant path synapses. J. Neurophysiol. In press
Ugolini A, Bordi F. 1995. Metabotropic
glutamate group II receptors are responsible for the depression of synaptic transmission induced by ACPD in the dentate
gyrus. Eur. J. Pharmacol. 294:403–10
Lanthorn TH, Ganong AH, Cotman CW.
1984. 2-amino-4-phosphonobutyrate blocks mossy fiber-CA3 responses in guinea
pig but not rat hippocampus. Brain Res.
290:174–78
Manzoni OJ, Castillo PE, Nicoll RA.
1995. Pharmacology of metabotropic glutamate receptors at the mossy fiber
synapses of the guinea pig hippocampus.
Neuropharmacology 34:965–71
Cao CQ, Evans RH, Headley PM, Udvarhelyi PM. 1995. A comparison of the
effects of selective metabotropic glutamate receptor agonists on synaptically
evoked whole cell currents of rat spinal
ventral horn neurones in vitro. Br. J. Pharmacol. 115:1469–74
Ishida M, Saitoh T, Shimamoto K, Ohfune Y, Shinozaki H. 1993. A novel
metabotropic glutamate receptor agonist:
marked depression of monosynaptic excitation in the newborn rat isolated spinal
cord. Br. J. Pharmacol. 109:1169–77
Lovinger DM, McCool BA. 1995. Metabotropic glutamate receptor-mediated
158.
159.
160.
161.
162.
163.
164.
165.
166.
167.
235
presynaptic depression at corticostriatal
synapses involves mGLuR2 or 3. J. Neurophysiol. 73:1076–83
Scanziani M, Gähwiler BH, Thompson
SM. 1995. Presynaptic inhibition of excitatory synaptic transmission by muscarinic and metabotropic glutamate receptor activation in the hippocampus: Are
Ca2+ channels involved?. Neuropharmacology 34:1549–57
Tyler EC, Lovinger DM. 1995. Metabotropic glutamate receptor modulation
of synaptic transmission in corticostriatal
co-cultures: role of calcium influx. Neuropharmacology 34:939–52
Sladeczek F, Momiyama A, Takahashi T.
1993. Presynaptic inhibitory action of a
metabotropic glutamate receptor agonist
on excitatory transmission in visual cortical neurons. Proc. R. Soc. London B
253:297–303
Winder PJ, Conn PJ. 1996. A novel form
of glial-neuronal communication mediated by coactivation of metabotropic glutamate receptors and β-adrenergic receptors in rat hippocampus. J. Physiol.
494:743–55
Gereau RW, Conn PJ. 1994. Potentiation of cAMP responses by metabotropic
glutamate receptors depresses excitatory
synaptic transmission by a kinase-independent mechanism. Neuron 12:1121–29
Herrero I, Miras-Portugal MT, SanchezPrieto J. 1992. Positive feedback of
glutamate exocytosis by metabotropic
presynaptic receptor stimulation. Nature
360:163–66
Collins DR, Davies SN. 1993. Co-administration of (1S, 3R)-1-aminocyclopentane-1, 3-dicarboxylic acid and arachidonic acid potentiates synaptic transmission in rat hippocampal slices. Eur. J.
Pharmacol. 240:325–26
Salt TE, Eaton SA. 1995. Distinct presynaptic metabotropic receptors for L-AP4
and CCG1 on GABAergic terminals:
pharmacological evidence using novel
α-methyl derivative mGluR antagonists,
MAP4 and MCCG, in the rat thalamus in
vivo. Neuroscience 65:5–13
Desai MA, McBain C, Kauer JA, Conn
PJ. 1994. Metabotropic glutamate receptor induced disinhibition is mediated
by reduced transmission at excitatory
synapses onto interneurons and inhibitory
synapses onto pyramidal cells. Neurosci.
Lett. 181:78–82
Poncer J-C, Shinozaki H, Miles R. 1995.
Dual modulation of synaptic inhibition
by distinct metabotropic glutamate recep-
236
168.
169.
170.
171.
172.
173.
174.
175.
176.
177.
178.
CONN & PIN
tors in the rat hippocampus. J. Physiol.
485:121–34
Aniksztejn L, Bregestovski P, Ben-Ari Y.
1991. Selective activation of quisqualate
metabotropic receptor potentiates NMDA
but not AMPA responses. Eur. J. Pharmacol. 205:327–28
Fitzjohn SM, Irving AJ, Palmer MJ, Harvey J, Lodge D, et al. 1996. Activation of
group I mGluRs potentiates NMDA responses in rat hippocampal slices. Neurosci. Lett. 203:211–13
Aronica E, Dell’Albani P, Condorelli DF,
Nicoletti F, Hack N, et al. 1993. Mechanisms underlying developmental changes
in the expression of metabotropic glutamate receptors in cultured cerebellar
granule cells: homologous desensitization and interactive effects involving N methyl-D-aspartate receptors. Mol. Pharmacol. 44:981–89
Rahman S, Neuman RS. 1996. Characterization of metabotropic glutamate
receptor-mediated facilitation of N-methyl-D-aspartate depolarization of neocortical neurones. Br. J. Pharmacol.
117:675–83
Bleakman D, Rusin KI, Chard PS, Glaum
SR, Miller RJ. 1992. Metabotropic glutamate receptors potentiate ionotropic glutamate responses in the rat dorsal horn.
Mol. Pharmacol. 42:192–96
Cerne R, Randic M. 1992. Modulation
of AMPA and NMDA responses in rat
spinal dorsal horn neurons by trans1-aminocyclopentane-1, 3-dicarboxylic
acid. Neurosci. Lett. 144:180–84
Colwell CS, Levine MS. 1994. Metabotropic glutamate receptors modulate
N -methyl-D-aspartate receptor function
in neostriatal neurons. Neuroscience
61:497–507
Copani A, Bruno VMG, Barresi V,
Battaglia G, Condorelli DF, et al. 1995.
Activation of metabotropic glutamate receptors prevents neuronal apoptosis in
culture. J. Neurochem. 64:101–8
Maiese K, Greenberg R, Boccone L,
Swiriduk M. 1995. Activation of the
metabotropic glutamate receptor is neuroprotective during nitric oxide toxicity
in primary hippocampal neurons of rats.
Neurosci. Lett. 194:173–76
Buisson A, Yu SP, Choi DW. 1996. DCGIV selectively attenuates rapidly triggered
NMDA-induced neurotoxicity in cortical
neurons. Eur. J. Neurosci. 8:138–43
Bruno V, Copani A, Knöpfel T, Kuhn
R, Casabona G, et al. 1995. Activation
of metabotropic glutamate receptors coupled to inositol phospholipid hydrolysis
179.
180.
181.
182.
183.
184.
185.
186.
187.
188.
189.
amplifies NMDA-induced neuronal degeneration in cultured cortical cells. Neuropharmacology 34:1089–98
Gallagher JP, Zheng F, Shinnick-Gallagher P. 1994. Long-lasting modulation
of synaptic transmission by metabotropic
glutamate receptors. In The Metabotropic Glutamate Receptors, ed. PJ Conn,
J Patel, pp. 173–93. Totowa, NJ: Humana
Conn PJ, Winder DG, Gereau RW IV.
1994. Regulation of neuronal circuits and
animal behavior by metabotropic glutamate receptors. In The Metabotropic Glutamate Receptors, ed. PJ Conn, J Patel,
pp. 195–229. Totowa, NJ: Humana
Riedel G, Wetzel W, Reymann KG.
1994. (R, S)-α-methyl-4-carboxyphenylglycine (MCPG) blocks spatial learning
in rats and long-term potentiation in the
dentate gyrus in vivo. Neurosci. Lett.
167:141–44
Ohno M, Watanabe S. 1996. Concurrent
blockade of hippocampal metabotropic
glutamate and N -methyl-D-aspartate receptors disrupts working memory in the
rat. Neuroscience 70:303–11
Van der Staay FJ, Antonicek H, Helpap B,
Freund WD. 1995. Effects of the selective
metabotropic glutamate receptor agonist,
L-CCG-I, on acquisition of a Morris task
by rats. Eur. J. Pharmacol. 294:361–65
Copani A, Bruno V, Battaglia G, Leanza
G, Pellitteri R, et al. 1995. Activation
of metabotropic glutamate receptors protects cultured neurons against apoptosis induced by β-amyloid peptide. Mol.
Pharmacol. 47:890–97
Lee RKK, Wurtman RJ, Cox AJ, Nitsch
RM. 1995. Amyloid precursor protein
processing is stimulated by metabotropic
glutamate receptors. Proc. Natl. Acad.
Sci. USA 92:8083–87
Sacaan AI, Schoepp DD. 1992. Activation
of hippocampal metabotropic excitatory
amino acid receptors leads to seizures and
neuronal damage. Neurosci. Lett. 139:77–
81
Tizzano JP, Griffey KI, Schoepp DD.
1995. Induction or protection of limbic seizures in mice by mGluR subtype
selective agonists. Neuropharmacology
34:1063–67
Klitgaard H, Laudrup P. 1993. Metabotropic excitatory amino acid receptor
agonists selectively potentiate behavioral
effects induced by ionotropic excitatory
amino acid receptor agonists in mice. Eur.
J. Pharmacol. 250:9–13
Thomsen C, Klitgaard H, Sheardown M,
Jackson HC, Eskesen K, et al. 1994. (S)–
4-carboxy-3-hydroxyphenylglycine, an
METABOTROPIC GLUTAMATE RECEPTORS
190.
191.
192.
193.
194.
antagonist of metabotropic glutamate
receptor (mGluR)1a and an agonist of
mGluR2, protects against audiogenic
seizures in DBA/2 mice. J. Neurochem.
62:2492–95
Dalby NO, Thomsen C. 1996. Modulation of seizure activity in mice by
metabotropic glutamate receptor ligands.
J. Pharmacol. Exp. Ther. 276:516–22
Sacaan AI, Bymaster FP, Schoepp DD.
1992. Metabotropic glutamate receptor
activation produces extrapyramidal motor
system activation that is mediated by striatal dopamine. J. Neurochem. 59:245–51
Kaatz KW, Albin RL. 1995. Intrastriatal and intrasubthalamic stimulation of
metabotropic glutamate receptors: a behavioral and Fos immunohistochemical
study. Neuroscience 66:55–65
Klockgether T, Turski L. 1993. Toward
an understanding of the role of glutamate
in experimental parkinsonism: agonistsensitive sites in the basal ganglia. Ann.
Neurol. 34:585–93
Salt TE, Eaton SA. 1994. The function of metabotropic excitatory amino
acid receptors in synaptic transmission
195.
196.
197.
198.
237
in the thalamus: studies with novel phenylglycine antagonists. Neurochem. Int.
24:451–58
Young MR, Fleetwood-Walker SM,
Mitchell R, Dickinson T. 1995. The involvement of metabotropic glutamate receptors and their intracellular signalling
pathways in sustained nociceptive transmission in rat dorsal horn neurons. Neuropharmacology 34:1033–41
Neugebauer V, Lücke T, Schaible H-G.
1994. Requirement of metabotropic glutamate receptors for the generation of
inflammation-evoked hyperexcitability in
rat spinal cord neurons. Eur. J. Neurosci.
6:1179–86
Pawloski-Dahm C, Gordon FJ. 1992. Evidence for a kynurenate-insensitive glutamate receptor in nucleus tractus solitarii.
Am. J. Physiol. 262:H1611–15
D’Amico M, Berrino L, Pizzirusso A, De
Novellis V, Rossi F. 1996. Opposing effects on blood pressure following the activation of metabotropic and ionotropic
glutamate receptors in raphe obscurus in
the anaesthetized rat. Naunyn Schmiedebergs Arch. Pharmacol. 353:302–5