Title

Isolation and characterization of α-conotoxin LsIA with potent activity at nicotinic acetylcholine receptors

RIS ID

105235

Publication Details

Inserra, M. C., Kompella, S. N., Vetter, I., Brust, A., Daly, N. L., Cuny, H., Craik, D., Alewood, P. F., Adams, D. J. & Lewis, R. J. (2013). Isolation and characterization of α-conotoxin LsIA with potent activity at nicotinic acetylcholine receptors. Biochemical Pharmacology, 86 (6), 791-799.

Abstract

A new α-conotoxin LsIA was isolated from the crude venom of Conus limpusi using assay-guided RP-HPLC fractionation. Synthetic LsIA was a potent antagonist of α3β2, α3α5β2 and α7 nAChRs, with half-maximal inhibitory concentrations of 10, 31 and 10 nM, respectively. The structure of LsIA determined by NMR spectroscopy comprised a characteristic disulfide bond-stabilized α-helical structure and disordered N-terminal region. Potency reductions of up to 9-fold were observed for N-terminally truncated analogues of LsIA at α7 and α3β2 nAChRs, whereas C-terminal carboxylation enhanced potency 3-fold at α3β2 nAChRs but reduced potency 3-fold at α7 nAChRs. This study gives further insight into α-conotoxin pharmacology and the molecular basis of nAChR selectivity, highlighting the influence of N-terminal residues and C-terminal amidation on conotoxin pharmacology.

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Link to publisher version (DOI)

http://dx.doi.org/10.1016/j.bcp.2013.07.016