Analgesic conotoxins: Block and G protein-coupled receptor modulation of N-type (Ca V2.2) calcium channels

Adams, David J., Callaghan, Brid and Berecki, Geza (2012) Analgesic conotoxins: Block and G protein-coupled receptor modulation of N-type (Ca V2.2) calcium channels. British Journal of Pharmacology, 166 2: 486-500. doi:10.1111/j.1476-5381.2011.01781.x


Author Adams, David J.
Callaghan, Brid
Berecki, Geza
Title Analgesic conotoxins: Block and G protein-coupled receptor modulation of N-type (Ca V2.2) calcium channels
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 0007-1188
1476-5381
Publication date 2012
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1111/j.1476-5381.2011.01781.x
Open Access Status
Volume 166
Issue 2
Start page 486
End page 500
Total pages 15
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley & Sons
Subject 3004 Pharmacology
Abstract Conotoxins (conopeptides) are small disulfide bonded peptides from the venom of marine cone snails. These peptides target a wide variety of membrane receptors, ion channels and transporters, and have enormous potential for a range of pharmaceutical applications. Structurally related ω-conotoxins bind directly to and selectively inhibit neuronal (N)-type voltage-gated calcium channels (VGCCs) of nociceptive primary afferent neurones. Among these, ω-conotoxin MVIIA (Prialt) is approved by the Food and Drug Administration (FDA) as an alternative intrathecal analgesic for the management of chronic intractable pain, particularly in patients refractory to opioids. A series of newly discovered ω-conotoxins from Conus catus, including CVID-F, are potent and selective antagonists of N-type VGCCs. In spinal cord slices, these peptides reversibly inhibit excitatory synaptic transmission between primary afferents and dorsal horn superficial lamina neurones, and in the rat partial sciatic nerve ligation model of neuropathic pain, significantly reduce allodynic behaviour. Another family of conotoxins, the α-conotoxins, are competitive antagonists of mammalian nicotinic acetylcholine receptors (nAChRs). α-Conotoxins Vc1.1 and RgIA possess two disulfide bonds and are currently in development as a treatment for neuropathic pain. It was initially proposed that the primary target of these peptides is the α9α10 neuronal nAChR. Surprisingly, however, α-conotoxins Vc1.1, RgIA and PeIA more potently inhibit N-type VGCC currents via a GABA B GPCR mechanism in rat sensory neurones. This inhibition is largely voltage-independent and involves complex intracellular signalling. Understanding the molecular mechanisms of conotoxin action will lead to new ways to regulate VGCC block and modulation in normal and diseased states of the nervous system.
Keyword α-conotoxin
ω-conotoxin
dorsal root ganglion
G protein-coupled receptor
GABA B receptor
HEK293 cell
pain pathway
voltage-gated calcium channel
Xenopus oocyte
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collections: Queensland Brain Institute Publications
School of Biomedical Sciences Publications
 
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Created: Mon, 27 Oct 2014, 18:17:35 EST by Sylvie Pichelin on behalf of Queensland Brain Institute