Globular and ribbon isomers of Conus geographus α-conotoxins antagonize human nicotinic acetylcholine receptors

Abstract

The short disulfide-rich α-conotoxins derived from the venom of Conus snails comprise a conserved C^IC^II(m)C^III(n)C^IV cysteine framework (m and n, number of amino acids) and the majority antagonize nicotinic acetylcholine receptors (nAChRs). Depending on disulfide connectivity, α-conotoxins can exist as either globular (C^I-C^III, C^II-C^IV), ribbon (C^I-C^IV, C^II-C^III) or bead (C^I-C^II, C^III-C^IV) isomers. In the present study, C. geographus α-conotoxins GI, GIB, G1.5 and G1.9 were chemically synthesized as globular and ribbon isomers and their activity investigated at human nAChRs expressed in Xenopus oocytes using the two-electrode voltage clamp recording technique. Both the globular and ribbon isomers of the 3/5 (m/n) α-conotoxins GI and GIB selectively inhibit heterologous human muscle-type α1β1δε nAChRs, whereas G1.5, a 4/7 α-conotoxin, selectively antagonizes neuronal (non-muscle) nAChR subtypes particularly human α3β2, α7 and α9α10 nAChRs. In contrast, globular and ribbon isomers of G1.9, a novel C-terminal elongated 4/8 α-conotoxin exhibited no activity at the human nAChR subtypes studied. This study reinforces earlier observations that 3/5 α-conotoxins selectively target the muscle nAChR subtypes, although interestingly, GIB is also active at α7 and α9 α10 nAChRs. The 4/7 α-conotoxins target human neuronal nAChR subtypes whereas the pharmacology of the 4/8 α-conotoxin remains unknown.

Keywords: Cone snail; Conus geographus; Disulfide bond isomer; Electrophysiology; Nicotinic acetylcholine receptor; α-Conotoxin GI.