Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Neurosci
2008 Oct 22;2843:10943-51. doi: 10.1523/JNEUROSCI.3594-08.2008.
Show Gene links
Show Anatomy links
Analgesic alpha-conotoxins Vc1.1 and Rg1A inhibit N-type calcium channels in rat sensory neurons via GABAB receptor activation.
Callaghan B
,
Haythornthwaite A
,
Berecki G
,
Clark RJ
,
Craik DJ
,
Adams DJ
.
???displayArticle.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.
Abe,
Changes in expression of voltage-dependent ion channel subunits in dorsal root ganglia of rats with radicular injury and pain.
2002, Pubmed
Abe,
Changes in expression of voltage-dependent ion channel subunits in dorsal root ganglia of rats with radicular injury and pain.
2002,
Pubmed
Altier,
Targeting Ca2+ channels to treat pain: T-type versus N-type.
2004,
Pubmed
Altier,
ORL1 receptor-mediated internalization of N-type calcium channels.
2006,
Pubmed
Bell,
Cell-specific alternative splicing increases calcium channel current density in the pain pathway.
2004,
Pubmed
Bettler,
Molecular structure and physiological functions of GABA(B) receptors.
2004,
Pubmed
Blanchfield,
Synthesis, structure elucidation, in vitro biological activity, toxicity, and Caco-2 cell permeability of lipophilic analogues of alpha-conotoxin MII.
2003,
Pubmed
Castro,
G-protein-coupled GABAB receptors inhibit Ca2+ channels and modulate transmitter release in descending turtle spinal cord terminal synapsing motoneurons.
2007,
Pubmed
Cizkova,
Localization of N-type Ca2+ channels in the rat spinal cord following chronic constrictive nerve injury.
2002,
Pubmed
Clark,
The synthesis, structural characterization, and receptor specificity of the alpha-conotoxin Vc1.1.
2006,
Pubmed
,
Xenbase
Clark,
The three-dimensional structure of the analgesic alpha-conotoxin, RgIA.
2008,
Pubmed
Diversé-Pierluissi,
Novel form of crosstalk between G protein and tyrosine kinase pathways.
1997,
Pubmed
Dolphin,
Activation of calcium channel currents in rat sensory neurons by large depolarizations: effect of Guanine nucleotides and (-)-baclofen.
1990,
Pubmed
Dolphin,
Calcium channel currents and their inhibition by (-)-baclofen in rat sensory neurones: modulation by guanine nucleotides.
1987,
Pubmed
Dutton,
alpha-Conotoxins: nicotinic acetylcholine receptor antagonists as pharmacological tools and potential drug leads.
2001,
Pubmed
Ellison,
Alpha-RgIA: a novel conotoxin that specifically and potently blocks the alpha9alpha10 nAChR.
2006,
Pubmed
,
Xenbase
Emson,
GABA(B) receptors: structure and function.
2007,
Pubmed
Fujikawa,
GABAB-mediated upregulation of the high-voltage-activated Ca2+ channels in rat dorsal root ganglia.
1997,
Pubmed
Gehrmann,
Solution structure of alpha-conotoxin ImI by 1H nuclear magnetic resonance.
1999,
Pubmed
Guyon,
Modulation by different GABAB receptor types of voltage-activated calcium currents in rat thalamocortical neurones.
1995,
Pubmed
Harayama,
Inhibition of N- and P/Q-type calcium channels by postsynaptic GABAB receptor activation in rat supraoptic neurones.
1998,
Pubmed
Hatakeyama,
Differential nociceptive responses in mice lacking the alpha(1B) subunit of N-type Ca(2+) channels.
2001,
Pubmed
Hogg,
Single amino acid substitutions in alpha-conotoxin PnIA shift selectivity for subtypes of the mammalian neuronal nicotinic acetylcholine receptor.
1999,
Pubmed
Jakubowski,
Determining sequences and post-translational modifications of novel conotoxins in Conus victoriae using cDNA sequencing and mass spectrometry.
2004,
Pubmed
Jin,
Structure of alpha-conotoxin BuIA: influences of disulfide connectivity on structural dynamics.
2007,
Pubmed
,
Xenbase
Kim,
Altered nociceptive response in mice deficient in the alpha(1B) subunit of the voltage-dependent calcium channel.
2001,
Pubmed
Lang,
A conus peptide blocks nicotinic receptors of unmyelinated axons in human nerves.
2005,
Pubmed
Lewis,
Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes.
2000,
Pubmed
,
Xenbase
Livett,
Drugs from the sea: conopeptides as potential therapeutics.
2004,
Pubmed
Livett,
Therapeutic applications of conotoxins that target the neuronal nicotinic acetylcholine receptor.
2006,
Pubmed
McGivern,
Targeting N-type and T-type calcium channels for the treatment of pain.
2006,
Pubmed
McIntosh,
Conus peptides targeted to specific nicotinic acetylcholine receptor subtypes.
1999,
Pubmed
Menon-Johansson,
G(o) transduces GABAB-receptor modulation of N-type calcium channels in cultured dorsal root ganglion neurons.
1993,
Pubmed
Nevin,
Are alpha9alpha10 nicotinic acetylcholine receptors a pain target for alpha-conotoxins?
2007,
Pubmed
,
Xenbase
Puckerin,
Arrestin is required for agonist-induced trafficking of voltage-dependent calcium channels.
2006,
Pubmed
Raingo,
Alternative splicing controls G protein-dependent inhibition of N-type calcium channels in nociceptors.
2007,
Pubmed
Richman,
RGS12 interacts with the SNARE-binding region of the Cav2.2 calcium channel.
2005,
Pubmed
Richman,
Mapping of RGS12-Cav2.2 channel interaction.
2004,
Pubmed
Roussel,
Selective binding of activated pp60c-src by an immobilized synthetic phosphopeptide modeled on the carboxyl terminus of pp60c-src.
1991,
Pubmed
Saegusa,
Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N-type Ca2+ channel.
2001,
Pubmed
Sandall,
A novel alpha-conotoxin identified by gene sequencing is active in suppressing the vascular response to selective stimulation of sensory nerves in vivo.
2003,
Pubmed
Satkunanathan,
Alpha-conotoxin Vc1.1 alleviates neuropathic pain and accelerates functional recovery of injured neurones.
2005,
Pubmed
Schuler,
Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABA(B) responses in mice lacking GABA(B(1)).
2001,
Pubmed
Scroggs,
Calcium current variation between acutely isolated adult rat dorsal root ganglion neurons of different size.
1992,
Pubmed
Sharpe,
Allosteric alpha 1-adrenoreceptor antagonism by the conopeptide rho-TIA.
2003,
Pubmed
Strock,
Ca2+ channels as integrators of G protein-mediated signaling in neurons.
2004,
Pubmed
Szallasi,
Vanilloid (Capsaicin) receptors and mechanisms.
1999,
Pubmed
Terlau,
Conus venoms: a rich source of novel ion channel-targeted peptides.
2004,
Pubmed
Tombler,
G protein-induced trafficking of voltage-dependent calcium channels.
2006,
Pubmed
Vincler,
Molecular mechanism for analgesia involving specific antagonism of alpha9alpha10 nicotinic acetylcholine receptors.
2006,
Pubmed
Vincler,
Targeting the alpha9alpha10 nicotinic acetylcholine receptor to treat severe pain.
2007,
Pubmed
Walwyn,
Beta-arrestin2 and c-Src regulate the constitutive activity and recycling of mu opioid receptors in dorsal root ganglion neurons.
2007,
Pubmed
Yang,
[Current responses mediated by endogenous GABA(B) and GABA(C) receptors in Xenopus oocytes].
2001,
Pubmed
,
Xenbase
Yasuda,
Auxiliary subunit regulation of high-voltage activated calcium channels expressed in mammalian cells.
2004,
Pubmed
,
Xenbase
Yokoyama,
Plastic change of N-type Ca channel expression after preconditioning is responsible for prostaglandin E2-induced long-lasting allodynia.
2003,
Pubmed