Maurotoxin

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Maurotoxin is a toxin from the venom of the scorpion Scorpio maurus palmatus. It acts by blocking several voltage-dependent potassium channels.

Etymology and source

The word maurotoxin is derived from the source from which it was first isolated, the Tunisian chactoid scorpion, Scorpio maurus palmatus.

Chemistry

Maurotoxin is a basic 34 amino acids toxin. It is cross-linked by four disulfide bridges, with an atypical pattern of organization compared with conventional three-disulfide-bridged scorpion toxins. The α-helix of MTX is connected by two disulfide bridges to two different strands of the β-sheet, instead of connecting the α-helix to the same strand.

Target

Scorpion toxins constitute the largest group of potassium (K⁺) channel blockers and are useful pharmacological probes to investigate ion channels and their functions.

Maurotoxin (MTX) blocks various K⁺ -channels:

• Apamin-sensitive small conductance Ca²⁺ - activated K⁺ channels (SK)
• Intermediate conductance Ca²⁺ - activated K⁺ channels (IK)
• Several types of voltage-gated Kv channels (Kv1.1, Kv1.2, Kv1.3 and shaker B)

The structural and pharmacological features of MTX suggest that MTX belongs to a new class of natural K⁺ channel blockers structurally intermediate between the Na⁺ (60–70 residues and four disulfide bridges) and K⁺ channel scorpion toxin families (less than 40 residues and three disulfide bridges).

The intermediate conductance Ca²⁺-activated K⁺ (IK) channel is present in peripheral tissues, including secretory epithelia and blood cells. An important physiological role of the IK channel is to help maintain large electrical gradients for the sustained transport of ions such as Ca²⁺ that controls T lymphocyte (T cell) proliferation. Hereby IK blockers could be potential immunosuppressants for the treatment of autoimmune disorders (such as rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis).

Mode of action

MTX occludes the pore region of various potassium channels (Kv1.2, IKCa1, Kv1.3) by establishing strong interactions between its Lys23 residue and the GYGD motif of the channel. MTX thus blocks the channels by binding in the external vestibule of the pore to block the ion conduction pathway. Although Kv1.1, Kv1.2, and Kv1.3 have a very similar pore structure, they display different pharmacological sensitivity to MTX.

References

1. Carlier, E., et al., Effect of maurotoxin, a four disulfide-bridged toxin from the chactoid scorpion Scorpio maurus, on Shaker K+ channels. J Pept Res, 2000. 55(6): p. 419-27.
2. Castle, N.A., et al., Maurotoxin: a potent inhibitor of intermediate conductance Ca2+-activated potassium channels. Mol Pharmacol, 2003. 63(2): p. 409-18.
3. Fu, W., et al., Brownian dynamics simulations of the recognition of the scorpion toxin maurotoxin with the voltage-gated potassium ion channels. Biophys J, 2002. 83(5): p. 2370-85.
4. Jensen, B.S., et al., The Ca2+-activated K+ channel of intermediate conductance:a possible target for immune suppression. Expert Opin Ther Targets, 2002. 6(6): p. 623-36.
5. Kharrat, R., et al., Chemical synthesis and characterization of maurotoxin, a short scorpion toxin with four disulfide bridges that acts on K+ channels. Eur J Biochem, 1996. 242(3): p. 491-8.
6. M'Barek, S., et al., A maurotoxin with constrained standard disulfide bridging: innovative strategy of chemical synthesis, pharmacology, and docking on K+ channels. J Biol Chem, 2003. 278(33): p. 31095-104.
7. Rochat, H., et al., Maurotoxin, a four disulfide bridges scorpion toxin acting on K+ channels. Toxicon, 1998. 36(11): p. 1609-11.
8. Visan, V., et al., Mapping of maurotoxin binding sites on hKv1.2, hKv1.3, and hIKCa1 channels. Mol Pharmacol, 2004. 66(5): p. 1103-12.