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Analgesic alpha-conotoxins Vc1.1 and Rg1A inhibit N-type calcium channels in rat sensory neurons via GABAB receptor activation. | LitMetric

Analgesic alpha-conotoxins Vc1.1 and Rg1A inhibit N-type calcium channels in rat sensory neurons via GABAB receptor activation.

J Neurosci

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

Published: October 2008

AI Article Synopsis

  • Alpha-conotoxins Vc1.1 and Rg1A, derived from marine Conus snail venom, are being developed to treat neuropathic pain by inhibiting high-voltage-activated calcium channel currents in specific neurons.
  • Vc1.1 selectively targets the N-type calcium channels (Ca(V)2.2) through a unique voltage-independent mechanism that involves a G-protein-coupled receptor, rather than directly blocking the channels.
  • The inhibition of calcium currents by Vc1.1 and Rg1A is influenced by GABA(B) receptor antagonists, suggesting these conotoxins may exert their analgesic effects by acting as agon

Article Abstract

alpha-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 alpha9alpha10 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 alpha-conotoxins tested. Vc1.1 inhibited the omega-conotoxin-sensitive HVA currents in DRG neurons but not those recorded from Xenopus oocytes expressing Ca(V)2.2, Ca(V)2.1, Ca(V)2.3, or Ca(V)1.2 channels. Inhibition of HVA currents by Vc1.1 was not reversed by depolarizing prepulses but was abolished by pertussis toxin (PTX), intracellular GDPbetaS, 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(V)2.2 as a target of Vc1.1 and Rg1A, potentially mediating their analgesic actions. We propose a novel mechanism by which alpha-conotoxins Vc1.1 and Rg1A modulate native N-type (Ca(V)2.2) Ca2+ channel currents, namely acting as agonists via G-protein-coupled GABA(B) receptors.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6671365PMC
http://dx.doi.org/10.1523/JNEUROSCI.3594-08.2008DOI Listing

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