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Type: Journal article
Title: Structure-activity studies reveal the molecular basis for GABAB-receptor mediated inhibition of high voltage-activated calcium channels by α-conotoxin Vc1.1
Other Titles: Structure-activity studies reveal the molecular basis for GABAB-receptor mediated inhibition of high voltage-activated calcium channels by alpha-conotoxin Vc1.1
Author: Sadeghi, M.
Carstens, B.
Callaghan, B.
Daniel, J.
Tae, H.
O'Donnell, T.
Castro, J.
Brierley, S.
Adams, D.
Craik, D.
Clark, R.
Citation: ACS Chemical Biology, 2018; 13(6):1577-1587
Publisher: American Chemical Society
Issue Date: 2018
ISSN: 1554-8929
Statement of
Mahsa Sadeghi, Bodil B. Carstens, Brid P. Callaghan, James T. Daniel, Han-Shen Tae, Tracey O, Donnell, Joel Castro, Stuart M. Brierley, David J. Adams, David J. Craik, and Richard J. Clark
Abstract: α-Conotoxins are disulfide-bonded peptides from cone snail venoms and are characterized by their affinity for nicotinic acetylcholine receptors (nAChR). Several α-conotoxins with distinct selectivity for nAChR subtypes have been identified as potent analgesics in animal models of chronic pain. However, a number of α-conotoxins have been shown to inhibit N-type calcium channel currents in rodent dissociated dorsal root ganglion (DRG) neurons via activation of G protein-coupled GABAB receptors (GABABR). Therefore, it is unclear whether activation of GABABR or inhibition of α9α10 nAChRs is the analgesic mechanism. To investigate the mechanisms by which α-conotoxins provide analgesia, we synthesized a suite of Vc1.1 analogues where all residues, except the conserved cysteines, in Vc1.1 were individually replaced by alanine (A), lysine (K), and aspartic acid (D). Our results show that the amino acids in the first loop play an important role in binding of the peptide to the receptor, whereas those in the second loop play an important role for the selectivity of the peptide for the GABABR over α9α10 nAChRs. We designed a cVc1.1 analogue that is >8000-fold selective for GABABR-mediated inhibition of high voltage-activated (HVA) calcium channels over α9α10 nAChRs and show that it is analgesic in a mouse model of chronic visceral hypersensitivity (CVH). cVc1.1[D11A,E14A] caused dose-dependent inhibition of colonic nociceptors with greater efficacy in ex vivo CVH colonic nociceptors relative to healthy colonic nociceptors. These findings suggest that selectively targeting GABABR-mediated HVA calcium channel inhibition by α-conotoxins could be effective for the treatment of chronic visceral pain.
Keywords: Animals; Mice, Inbred C57BL; Xenopus laevis; Rats, Wistar; Pain; Calcium Channels, N-Type; Receptors, GABA-B; Receptors, Nicotinic; Nicotinic Antagonists; Analgesics; Calcium Channel Blockers; Conotoxins; Molecular Structure; Structure-Activity Relationship; Male
Description: Published: May 10, 2018
Rights: © 2018 American Chemical Society
RMID: 0030090312
DOI: 10.1021/acschembio.8b00190
Grant ID:
Appears in Collections:Molecular and Biomedical Science publications

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