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The Journal of Neuroscience, October 22, 2008, 28(43):10943-10951; doi:10.1523/JNEUROSCI.3594-08.2008

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Cellular/Molecular
Analgesic -Conotoxins Vc1.1 and Rg1A Inhibit N-Type Calcium Channels in Rat Sensory Neurons via GABA_B Receptor Activation

Brid Callaghan,¹ Alison Haythornthwaite,¹ Géza Berecki,¹ Richard J. Clark,² David J. Craik,² and David J. Adams¹

¹Queensland Brain Institute and School of Biomedical Sciences, and ²Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia

Correspondence should be addressed to Dr. David J. Adams, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia. Email: dadams{at}uq.edu.au

-Conotoxins Vc1.1 and Rg1A are peptides from the venom of marine Conus snails that are currently in development as a treatment for neuropathic pain. Here we report that the 910 nicotinic acetylcholine receptor-selective conotoxins Vc1.1 and Rg1A potently and selectively inhibit high-voltage-activated (HVA) calcium channel currents in dissociated DRG neurons in a concentration-dependent manner. The post-translationally modified peptides vc1a and [P6O]Vc1.1 were inactive, as were all other -conotoxins tested. Vc1.1 inhibited the -conotoxin-sensitive HVA currents in DRG neurons but not those recorded from Xenopus oocytes expressing Ca_V2.2, Ca_V2.1, Ca_V2.3, or Ca_V1.2 channels. Inhibition of HVA currents by Vc1.1 was not reversed by depolarizing prepulses but was abolished by pertussis toxin (PTX), intracellular GDPβS, or a selective inhibitor of pp60c-src tyrosine kinase. These data indicate that Vc1.1 does not interact with N-type calcium channels directly but inhibits them via a voltage-independent mechanism involving a PTX-sensitive, G-protein-coupled receptor. Preincubation with a variety of selective receptor antagonists demonstrated that only the GABA_B receptor antagonists, [S-(R*,R*)][-3-[[1-(3,4-dichlorophenyl)ethyl]amino]-2-hydroxy propyl]([3,4]-cyclohexylmethyl) phosphinic acid hydrochloride (2S)-3[[(1S)-1-(3,4-dichlorophenyl)-ethyl]amino-2-hydroxypropyl](phenylmethyl) phosphinic acid and phaclofen, blocked the effect of Vc1.1 and Rg1A on Ca²⁺ channel currents. Together, the results identify Ca_V2.2 as a target of Vc1.1 and Rg1A, potentially mediating their analgesic actions. We propose a novel mechanism by which -conotoxins Vc1.1 and Rg1A modulate native N-type (Ca_V2.2) Ca²⁺ channel currents, namely acting as agonists via G-protein-coupled GABA_B receptors.

Key words: conotoxins; N-type calcium channel; dorsal root ganglion; GABA_B receptor; G-protein; analgesia

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Received July 23, 2008; revised Aug. 30, 2008; accepted Sept. 8, 2008.

Correspondence should be addressed to Dr. David J. Adams, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia. Email: dadams{at}uq.edu.au

This article has been cited by other articles:

				R. Halai, R. J. Clark, S. T. Nevin, J. E. Jensen, D. J. Adams, and D. J. Craik Scanning Mutagenesis of {alpha}-Conotoxin Vc1.1 Reveals Residues Crucial for Activity at the {alpha}9{alpha}10 Nicotinic Acetylcholine Receptor J. Biol. Chem., July 24, 2009; 284(30): 20275 - 20284. [Abstract] [Full Text] [PDF]

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