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First published on September 5, 2007; DOI: 10.1124/mol.107.040568

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Received for publication August 6, 2007.
Revised September 4, 2007.
Accepted for publication September 5, 2007.

ARE {alpha}9{alpha}10 NICOTINIC ACETYLCHOLINE RECEPTORS A PAIN TARGET FOR {alpha}-CONOTOXINS?

Simon T. Nevin 1, Richard J. Clark 1, Harry Klimis 2, Macdonald J. Christie 2, David J. Craik 1, David J. Adams 1*

1 University of Queensland 2 University of Sydney

* Address correspondence to: E-mail: dadams{at}uq.edu.au

Abstract

The synthetic {alpha}-conotoxin Vc1.1 (ACV1) is a small disulfide bonded peptide currently in development as a treatment for neuropathic pain. Unlike Vc1.1, the native post-translationally-modified peptide vc1a does not act as an analgesic in vivo in rat models of neuropathic pain. Recently, it has been proposed that the primary target of Vc1.1 is the {alpha}9{alpha}10 nicotinic acetylcholine receptor (nAChR). We show that Vc1.1 and its post-translationally modified analogues vc1a, [P6O]Vc1.1 and [E14{gamma}]Vc1.1 are equally potent at inhibiting ACh-evoked currents mediated by {alpha}9{alpha}10 nAChRs. This suggests that {alpha}9{alpha}10 nAChRs are unlikely to be the molecular mechanism or therapeutic target of Vc1.1 for the treatment of neuropathic pain.


Key words: Nicotinic cholinergic, Structure-activity relationships and modeling




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