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      • Record: found
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      ω-Conotoxins GVIA, MVIIA and CVID: SAR and Clinical Potential

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          Abstract

          Highly selective N-type voltage-gated calcium (Ca V) channel inhibitors from cone snail venom (the ω-conotoxins) have emerged as a new class of therapeutics for the treatment of chronic and neuropathic pain. Earlier in 2005, Prialt (Elan) or synthetic ω-conotoxin MVIIA, was the first ω-conotoxin to be approved by Food and Drug Administration for human use. This review compares the action of three ω-conotoxins, GVIA, MVIIA and CVID, describing their structure-activity relationships and potential as leads for the design of improved N-type therapeutics that are more useful in the treatment of chronic pain.

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          A common structural motif incorporating a cystine knot and a triple-stranded beta-sheet in toxic and inhibitory polypeptides.

          P K Pallaghy, K J Nielsen, D J Craik … (1994)
          A common structural motif consisting of a cystine knot and a small triple-stranded beta-sheet has been defined from comparison of the 3-dimensional structures of the polypeptides omega-conotoxin GVIA (Conus geographus), kalata BI (Oldenlandia affinis DC), and CMTI-I (Curcurbita maxima). These 3 polypeptides have diverse biological activities and negligible amino acid sequence identity, but each contains 3 disulfide bonds that give rise to a cystine knot. This knot consists of a ring formed by the first 2 bonds (1-4 and 2-5) and the intervening polypeptide backbone, through which the third disulfide (3-6) passes. The other component of this motif is a triple-stranded, anti-parallel beta-sheet containing a minimum of 10 residues, XXC2, XC5X, XXC6X (where the numbers on the half-cysteine residues refer to their positions in the disulfide pattern). The presence in these polypeptides of both the cysteine knot and antiparallel beta-sheet suggests that both structural features are required for the stability of the motif. This structural motif is also present in other protease inhibitors and a spider toxin. It appears to be one of the smallest stable globular domains found in proteins and is commonly used in toxins and inhibitors that act by blocking the function of larger protein receptors such as ion channels or proteases.
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            Structure and function of voltage-gated ion channels.

            W Catterall (1994)
            Voltage-gated ion channels are responsible for generation of electrical signals in cell membranes. Their principal subunits are members of a gene family and can function as voltage-gated ion channels by themselves. They are expressed in association with one or more auxiliary subunits which increase functional expression and modify the functional properties of the principal subunits. Structural elements that are required for voltage-dependent activation, selective ion conductance, and inactivation have been identified, and their mechanisms of action are being explored through mutagenesis, expression in heterologous cells, and functional analysis. These experiments reveal that this family of channels is built upon a common structural theme with variations appropriate for functional specialization of each channel type.
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              Roles of N-type and Q-type Ca2+ channels in supporting hippocampal synaptic transmission.

              D. Wheeler, A. Randall, R Tsien (1994)
              Several types of calcium channels found in the central nervous system are possible participants in triggering neurotransmitter release. Synaptic transmission between hippocampal CA3 and CA1 neurons was mediated by N-type calcium channels, together with calcium channels whose pharmacology differs from that of L- and P-type channels but resembles that of the Q-type channel encoded by the alpha 1A subunit gene. Blockade of either population of channels strongly increased enhancement of synaptic transmission with repetitive stimuli. Even after complete blockade of N-type channels, transmission was strongly modulated by stimulation of neurotransmitter receptors or protein kinase C. These findings suggest a role for alpha 1A subunits in synaptic transmission and support the idea that neurotransmitter release may depend on multiple types of calcium channels under physiological conditions.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mar Drugs
                Journal ID (iso-abbrev): Mar Drugs
                Journal ID (publisher-id): MD
                Title: Marine Drugs
                Publisher: Molecular Diversity Preservation International (MDPI)
                ISSN (Electronic): 1660-3397
                Publication date Collection: April 2006
                Publication date (Electronic): 06 April 2006
                Volume: 4
                Issue: 3
                Pages: 193-214
                Affiliations
                Institute for Molecular Bioscience, The University of Queensland, St Lucia, 4072, QLD, Australia, E-mail: t.schroeder@ 123456imb.uq.edu.au (for Christina I. Schroeder)
                Author notes
                [* ]To whom correspondence should be addressed. Tel: +61-7-3346 2984; Fax: +61-7-3346 2101. E-mail: r.lewis@ 123456imb.uq.edu.au
                Article
                Publisher ID: marinedrugs-04-00193
                PMC ID: 3663408
                SO-VID: f23da5a1-b8d8-4110-8be7-5996e0ef18eb
                Copyright © © 2006 by MDPI
                License:

                Reproduction is permitted for noncommercial purposes.

                History
                Date received : 16 February 2006
                Date accepted : 28 February 2006
                Categories
                Subject: Review

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: structure-activity relationship,pain,ω-conotoxin
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: structure-activity relationship, pain, ω-conotoxin

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