Mu - Conotoxins and the Voltage-Gated Sodium Channel

This sodium channel is composed of three polypeptide subunits , alpha (subunit molecular weight ~260 kDa), beta1 (36 kDa) and beta2 (33kDa) (Catterall 1984). The toxin binding sites are located on the alpha subunit which consists of four homologous domains (I-IV) each of 300-200 amino acids and containing six transmembrane helices (S1-S6) that associate to form a barrel like structure around the fourth of the six helices. The fourth helix is relatively charged, and it is thought that this is the 'chemosensory' part of the channel, changing conformationally in response to changes in electric field regulating the influx of sodium into the cell.

In addition there is a seventh region (SS1-SS2) which is thought to lie within the plane of the membrane and possesses a beta sheet conformation to which tetrodotoxin (TTX) and alpha scorpion toxins bind.

Mu - Conotoxins

The mu-conotoxins GIIIA , GIIIB and GIIIC are hydroxyproline-rich basic peptides of 22 amino acids. The peptides contain 3 hydroxyprolines and 6 cysteines. The presence of several lys and Arg residues confers a high positive charge of +6 in GIIIA and +7 in GIIIB and GIIIC.

They act upon sodium channels in muscle , and also to a very limited extent in neurons, where they bind to a site designated 'binding site one' at the mouth of the sodium channel , and thus inhibit the influx of sodium into the cell which renders the organism paralysed.

The 22 residue mu-conotoxin (from conus geographus - known as geographutoxin) is a competitive inhibitor of the binding of saxitoxin (STX) and derivatives to the sodium channels in muscle but not in nerve. In contrast to TTX and STX the binding of mu-conotoxin is voltage-dependent This toxin discriminates between nerve and muscle sodium channels which otherwise show very little difference in their kinetics and in their responses to TTX and STX. Cardiac "TTX-resistant" sodium channels are also refractory to mu-conotoxins indicating that mu-conotoxin and the structurally unrelated STX/TTX toxins all bind to common or overlapping sites on the sodium channel (Gray and Olivera 1988). Studies with synthetic analogues of GIIIA point to the importance of Arg13 for the blocking of the sodium channel pore. The residues most important for activity are Arg13, Lys16, Hyp17 and Arg19, and 3D molecular modeling studies show that these all face one side of mu-conotoxin GIIIA which is presumed to bind with the active site of the channel. Binding of the mu-conotoxins to mutants of sodium channels has been used to map the amino acid residues important for their interaction with neurotoxin site 1 of voltage sensistive sodium channels (Stephan et al 1994; Dudley, et al 1995).

A polypeptide delta-conotoxin (TxVIA) from Conus textile that is selectively active on molluscs appears to have a distinct binding site on the sodium channel through which it mediates sodium channel inactivation (Fainzilber et al 1994).

More recently, a mu-conotoxin from Conus purpurascens was discovered by Olivera and coworkers (Shon et al 1996) by sequencing the toxin gene. This new mu-toxin (mu-PIIIA) was then chemically synthesized and shown to reversibly block the type II Na channel of rat brain, which is TTX sensitive but resistant to the mu-conotoxin, mu-GIIIA, from Conus geographus.

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CG and BGL, December-97

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