Solution Structure of μ-Conotoxin PIIIA, a Selective Inhibitor of Persistent TTX-Sensitive Sodium Channels

μ-Conotoxins are peptide inhibitors of voltage-sensitive sodium channels (VSSCs). Synthetic forms of PIIIA and PIIIA(2-22) were found to inhibit TTX-sensitive VSSC current but had little effect on TTXresistant VSSC current in peripheral ganglia. In rat brain neurons, these peptides preferentially inhibited the persistent over the transient VSSC current. Radioligand binding assays revealed that PIIIA, PIIIA(2-22) and μ-conotoxin GIIIB discriminated among TTX-sensitive VSSCs in rat brain, that these and GIIIC discriminated among the corresponding VSSCs in human brain, while GIIIA had low affinity for neuronal VSSCs. H NMR studies revealed that PIIIA adopts two conformations in solution due to cis/trans isomerisation at hydroxyproline8. The major trans conformation results in a 3D structure that is significantly different from the major conformation of other μ-conotoxins that selectively target TTX-sensitive muscle VSSCs. Comparison of the structures and activity of PIIIA to muscle-selective μ-conotoxins provides an insight into the structural requirements for inhibition of different TTX-sensitive sodium channels by μ-conotoxins.