μ-Conotoxin KIIIA

µ-conotoxin KIIIA is a potent Nav1.2 blocker. µ-conotoxin KIIIA was originally identified within the venom of the marine fish-hunting cone snail Conus kinoshitai. The peptide has 16 amino acid residues and possesses 3 disulfide bridges originally assumed to be connected along the following pattern: Cys1-Cys9, Cys2-Cys15, and Cys4-Cys16. Upon chemical synthesis, the major isoform possesses in fact the Cys1-Cys15, Cys2-Cys9 and Cys4-Cys16 connectivity, the one with the most potent pharmacological activity. The peptide was found to possess potent analgesic activity inflammatory pain (formalin test) without producing motor impairment. ED50 was 0.1 mg/kg by intraperitoneal injection. In mouse DRG neurons, 5 mM m-conotoxin KIIIA blocks over 50% TTX-sensitive voltage-gated sodium currents, while marginally affecting 20% of the TTX-resistant current. The toxin blocked the various Nav isoforms with the following rank of potencies: rat Nav1.2 (Kd of 3 nM) > rat Nav1.4 (Kd of 50 nM) > rat Nav1.1 (Kd of 290 nM) = rat Nav1.7 >> rat Nav1.3 (Kd of 8 mM). Rat Nav1.5 and Nav1.8 seemed not affected by the peptide. A particularity of the Nav1.2 block is that it is irreversible contrary to other Nav isoform blockades. This irreversible block relies on Trp8. The mature peptide sequence of m-conotoxin KIIIA produced in the venom of Conus kinoshitai possesses two additional residues preceding the N-terminus (Asn1 and Gly2) forming an extended N-terminal isoform that was termed m-conotoxin KIIIB. m-conotoxin KIIIA interacts with the extracellular segments in repeats I, II and III of Nav1.2 with Lys7 blocking Na+ entry to the Na+ binding site within the selectivity filter vestibule