N- and C-terminal extensions of μ-conotoxins increase potency and selectivity for neuronal sodium channels.
μ-Conotoxins are peptide blockers of voltage-gated sodium channels (sodium channels), inhibiting tetrodotoxin-sensitive neuronal (Na(v) 1.2) and skeletal (Na(v) 1.4) subtypes with highest affinity. Structure-activity relationship studies of μ-conotoxins SIIIA, TIIIA, and KIIIA have shown that it is mainly the C-terminal part of the three-loop peptide that is involved in binding to the sodium channel. In this study, we characterize the effect of N- and C-terminal extensions of μ-conotoxins SIIIA, SIIIB, and TIIIA on their potency and selectivity for neuronal versus muscle sodium channels. Interestingly, extending the N- or C-terminal of the peptide by introducing neutral, positive, and/or negatively charged residues, the selectivity of the native peptide can be altered from neuronal to skeletal and the other way around. The results from this study provide further insight into the binding profile of μ-conotoxins at voltage-gated sodium channels, revealing that binding interactions outside the cysteine-stablilized loops can contribute to μ-conotoxin affinity and sodium channel selectivity.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
Christina I
CI
Schroeder
Denise
D
Adams
Linda
L
Thomas
Paul F
PF
Alewood
Richard J
RJ
Lewis
D000818:Animals; D020916:Conotoxins / Q000737:chemistry*; D052078:Conus Snail / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008978:Mollusk Venoms / Q000737:chemistry; D009132:Muscles / Q000737:chemistry*; D009474:Neurons / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D051381:Rats; D012680:Sensitivity and Specificity; D015222:Sodium Channels / Q000737:chemistry*; D013329:Structure-Activity Relationship
D020916:Conotoxins; D008978:Mollusk Venoms; D010455:Peptides; D015222:Sodium Channels