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

Callaghan, Brid, Haythornthwaite, Alison R., Berecki, Geza, Clark, Richard J., Craik, David J. and Adams, David J. (2008) Analgesic alpha-Conotoxins Vc1.1 and Rg1A inhibit N-type calcium channels in rat sensory neurons via GABA-B receptor activation. The Journal of Neuroscience, 28 43: 10943-10951. doi:10.1523/JNEUROSCI.3594-08.2008

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Author Callaghan, Brid
Haythornthwaite, Alison R.
Berecki, Geza
Clark, Richard J.
Craik, David J.
Adams, David J.
Title Analgesic alpha-Conotoxins Vc1.1 and Rg1A inhibit N-type calcium channels in rat sensory neurons via GABA-B receptor activation
Formatted title
Analgesic α-Conotoxins Vc1.1 and Rg1A inhibit N-type calcium channels in rat sensory neurons via GABAŠ² receptor activation
Journal name The Journal of Neuroscience   Check publisher's open access policy
ISSN 0270-6474
1529-2401
Publication date 2008-10-22
Sub-type Article (original research)
DOI 10.1523/JNEUROSCI.3594-08.2008
Open Access Status File (Publisher version)
Volume 28
Issue 43
Start page 10943
End page 10951
Total pages 9
Editor John H. R. Maunsell
Place of publication Washington, DC, U.S.A.
Publisher Society for Neuroscience
Collection year 2009
Language eng
Subject C1
1109 Neurosciences
920111 Nervous System and Disorders
Formatted 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 {alpha}9{alpha}10 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 CaV2.2, CaV2.1, CaV2.3, or CaV1.2 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 GABAB 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 CaV2.2 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 (CaV2.2) Ca2+ channel currents, namely acting as agonists via G-protein-coupled GABAB receptors.
Keyword Conotoxins
N-type calcium channel
Dorsal root ganglion
GABAB receptor
G-protein
Analgesia
Q-Index Code C1
Q-Index Status Confirmed Code

 
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Created: Thu, 05 Mar 2009, 17:11:24 EST by Debra McMurtrie on behalf of Queensland Brain Institute