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      Scorpion Toxin, BmP01, Induces Pain by Targeting TRPV1 Channel

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          Abstract

          The intense pain induced by scorpion sting is a frequent clinical manifestation. To date, there is no established protocol with significant efficacy to alleviate the pain induced by scorpion envenomation. One of the important reasons is that, little information on pain-inducing compound from scorpion venoms is available. Here, a pain-inducing peptide (BmP01) has been identified and characterized from the venoms of scorpion ( Mesobuthus martensii). In an animal model, intraplantar injection of BmP01 in mouse hind paw showed significant acute pain in wild type (WT) mice but not in TRPV1 knock-out (TRPV1 KO) mice during 30 min recording. BmP01 evoked currents in WT dorsal root ganglion (DRG) neurons but had no effect on DRG neurons of TRPV1 KO mice. Furthermore, BmP01 evoked currents on TRPV1-expressed HEK293T cells, but not on HEK293T cells without TRPV1. These results suggest that (1) BmP01 is one of the pain-inducing agents in scorpion venoms; and (2) BmP01 induces pain by acting on TRPV1. To our knowledge, this is the first report about a scorpion toxin that produces pain by targeting TRPV1. Identification of a pain-inducing compound may facilitate treating pain induced by scorpion envenomation.

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          Most cited references46

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          Conus venoms: a rich source of novel ion channel-targeted peptides.

          The cone snails (genus Conus) are venomous marine molluscs that use small, structured peptide toxins (conotoxins) for prey capture, defense, and competitor deterrence. Each of the 500 Conus can express approximately 100 different conotoxins, with little overlap between species. An overwhelming majority of these peptides are probably targeted selectively to a specific ion channel. Because conotoxins discriminate between closely related subtypes of ion channels, they are widely used as pharmacological agents in ion channel research, and several have direct diagnostic and therapeutic potential. Large conotoxin families can comprise hundreds or thousands of different peptides; most families have a corresponding ion channel family target (i.e., omega-conotoxins and Ca channels, alpha-conotoxins and nicotinic receptors). Different conotoxin families may have different ligand binding sites on the same ion channel target (i.e., mu-conotoxins and delta-conotoxins to sites 1 and 6 of Na channels, respectively). The individual peptides in a conotoxin family are typically each selectively targeted to a diverse set of different molecular isoforms within the same ion channel family. This review focuses on the targeting specificity of conotoxins and their differential binding to different states of an ion channel.
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            A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain.

            Toxins have evolved to target regions of membrane ion channels that underlie ligand binding, gating, or ion permeation, and have thus served as invaluable tools for probing channel structure and function. Here, we describe a peptide toxin from the Earth Tiger tarantula that selectively and irreversibly activates the capsaicin- and heat-sensitive channel, TRPV1. This high-avidity interaction derives from a unique tandem repeat structure of the toxin that endows it with an antibody-like bivalency. The "double-knot" toxin traps TRPV1 in the open state by interacting with residues in the presumptive pore-forming region of the channel, highlighting the importance of conformational changes in the outer pore region of TRP channels during activation. Copyright 2010 Elsevier Inc. All rights reserved.
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              Molecular basis for species-specific sensitivity to "hot" chili peppers.

              Chili peppers produce the pungent vanilloid compound capsaicin, which offers protection from predatory mammals. Birds are indifferent to the pain-producing effects of capsaicin and therefore serve as vectors for seed dispersal. Here, we determine the molecular basis for this species-specific behavioral response by identifying a domain of the rat vanilloid receptor that confers sensitivity to capsaicin to the normally insensitive chicken ortholog. Like its mammalian counterpart, the chicken receptor is activated by heat or protons, consistent with the fact that both mammals and birds detect noxious heat and experience thermal hypersensitivity. Our findings provide a molecular basis for the ecological phenomenon of directed deterence and suggest that the capacity to detect capsaicin-like inflammatory substances is a recent acquisition of mammalian vanilloid receptors.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Toxins (Basel)
                Toxins (Basel)
                toxins
                Toxins
                MDPI
                2072-6651
                14 September 2015
                September 2015
                : 7
                : 9
                : 3671-3687
                Affiliations
                [1 ]Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China; E-Mails: hakeem.geb.ru@ 123456gmail.com (M.A.H.); aleismile@ 123456126.com (L.L.); 13700675996@ 123456126.com (B.L.)
                [2 ]Graduate University of Chinese Academy of Sciences, Beijing 100049, China
                [3 ]Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650223, China; E-Mail: sewend@ 123456163.com
                [4 ]Joint Laboratory of Natural Peptide, University of Science and Technology of China and Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
                Author notes
                [†]

                These authors contributed equally to this work.

                [* ]Authors to whom correspondence should be addressed; E-Mails: yslzoology@ 123456163.com (S.Y.); yuzhusong@ 123456kmust.edu.cn (Y.S.); rlai@ 123456mail.kiz.ac.cn (R.L.); Tel.: +86-871-6519-6202 (S.Y.); +86-871-6593-9528 (Y.S.); +86-871-6519-9086 (R.L.); Fax: +86-871-6519-9086 (S.Y. & R.L.); +86-871-6519-8622 (Y.S.).
                Article
                toxins-07-03671
                10.3390/toxins7093671
                4591660
                26389953
                b339fb6a-74e5-46ac-854f-0e0df1fc8226
                © 2015 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 06 August 2015
                : 07 September 2015
                Categories
                Article

                Molecular medicine
                scorpion mesobuthus martensii,peptide toxin,bmp01,kv channels,trpv1,pain
                Molecular medicine
                scorpion mesobuthus martensii, peptide toxin, bmp01, kv channels, trpv1, pain

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