{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T23:48:49Z","timestamp":1789516129223,"version":"build-2803163510"},"reference-count":51,"publisher":"Rockefeller University Press","issue":"5","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2000,11,1]]},"abstract":"<jats:p>The gating modifier toxins are a large family of protein toxins that modify either activation or inactivation of voltage-gated ion channels. \u03c9-Aga-IVA is a gating modifier toxin from spider venom that inhibits voltage-gated Ca2+ channels by shifting activation to more depolarized voltages. We identified two Glu residues near the COOH-terminal edge of S3 in the \u03b11A Ca2+ channel (one in repeat I and the other in repeat IV) that align with Glu residues previously implicated in forming the binding sites for gating modifier toxins on K+ and Na+ channels. We found that mutation of the Glu residue in repeat I of the Ca2+ channel had no significant effect on inhibition by \u03c9-Aga-IVA, whereas the equivalent mutation of the Glu in repeat IV disrupted inhibition by the toxin. These results suggest that the COOH-terminal end of S3 within repeat IV contributes to forming a receptor for \u03c9-Aga-IVA. The strong predictive value of previous mapping studies for K+ and Na+ channel toxins argues for a conserved binding motif for gating modifier toxins within the voltage-sensing domains of voltage-gated ion channels.<\/jats:p>","DOI":"10.1085\/jgp.116.5.637","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:50:20Z","timestamp":1027702220000},"page":"637-644","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":89,"title":["A Hot Spot for the Interaction of Gating Modifier Toxins with Voltage-Dependent Ion Channels"],"prefix":"10.1085","volume":"116","author":[{"given":"Jeffrey R.","family":"Winterfield","sequence":"first","affiliation":[{"name":"aMolecular Physiology and Biophysics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenton J.","family":"Swartz","sequence":"additional","affiliation":[{"name":"aMolecular Physiology and Biophysics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2000,10,16]]},"reference":[{"key":"2023072520270779600_ArmstrongandHille1998","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/S0896-6273(00)80981-2","article-title":"Voltage-gated ion channels and electrical excitability","volume":"20","author":"Armstrong","year":"1998","journal-title":"Neuron."},{"key":"2023072520270779600_Bourinetetal1999","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/8070","article-title":"Splicing of alpha 1A subunit gene generates phenotypic variants of P- and Q-type calcium channels","volume":"2","author":"Bourinet","year":"1999","journal-title":"Nat. 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Biol. Chem."},{"key":"2023072520270779600_Fainzilberetal1995","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1074\/jbc.270.3.1123","article-title":"A new conotoxin affecting sodium current inactivation interacts with the delta-conotoxin receptor site","volume":"270","author":"Fainzilber","year":"1995","journal-title":"J. Biol. Chem."},{"key":"2023072520270779600_GonoiandHille1987","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1085\/jgp.89.2.253","article-title":"Gating of Na+ channels. Inactivation modifiers discriminate among models","volume":"89","author":"Gonoi","year":"1987","journal-title":"J. Gen. Physiol."},{"key":"2023072520270779600_HanckandSheets1995","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1085\/jgp.106.4.601","article-title":"Modification of inactivation in cardiac sodium channelsionic current studies with anthopleurin-A toxin","volume":"106","author":"Hanck","year":"1995","journal-title":"J. Gen. Physiol."},{"key":"2023072520270779600_Hansetal1999","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1016\/S0006-3495(99)77300-5","article-title":"Structural elements in domain IV that influence biophysical and pharmacological properties of human alpha1A-containing high-voltage-activated calcium channels","volume":"76","author":"Hans","year":"1999","journal-title":"Biophys. J."},{"key":"2023072520270779600_Hille1992","volume-title":"Ionic Channels of Excitable Membranes","author":"Hille","year":"1992","edition":"2nd ed"},{"key":"2023072520270779600_HongandMiller2000","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1085\/jgp.115.1.51","article-title":"The lipid\u2013protein interface of a Shaker K+ channel","volume":"115","author":"Hong","year":"2000","journal-title":"J. Gen. 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Pharmacol."},{"key":"2023072520270779600_McDonoughetal1997b","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1016\/S0006-3495(97)78854-4","article-title":"Alteration of P-type calcium channel gating by the spider toxin omega- Aga-IVA","volume":"72","author":"McDonough","year":"1997","journal-title":"Biophys. J."},{"key":"2023072520270779600_Mevesetal1986","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/j.1749-6632.1986.tb15565.x","article-title":"Interactions of scorpion toxins with the sodium channel","volume":"479","author":"Meves","year":"1986","journal-title":"Annu. NY Acad. Sci."},{"key":"2023072520270779600_Mevesetal1987","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/BF00583792","article-title":"Gating current experiments on frog nodes of Ranvier treated with Centruroides sculpturatus toxins or aconitine","volume":"409","author":"Meves","year":"1987","journal-title":"Pfl\u00fcgers Arch."},{"key":"2023072520270779600_Miller1995","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/0896-6273(95)90057-8","article-title":"The charybdotoxin family of K+ channel-blocking peptides","volume":"15","author":"Miller","year":"1995","journal-title":"Neuron."},{"key":"2023072520270779600_Mintzetal1992a","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/0896-6273(92)90223-Z","article-title":"P-type calcium channels in rat central and peripheral neurons","volume":"9","author":"Mintz","year":"1992","journal-title":"Neuron."},{"key":"2023072520270779600_Mintzetal1992b","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/355827a0","article-title":"P-type calcium channels blocked by the spider toxin omega-Aga-IVA","volume":"355","author":"Mintz","year":"1992","journal-title":"Nature."},{"key":"2023072520270779600_Monksetal1995","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/S0969-2126(01)00214-3","article-title":"Solution structure of the cardiostimulant polypeptide anthopleurin-B and comparison with anthopleurin-A","volume":"3","author":"Monks","year":"1995","journal-title":"Structure."},{"key":"2023072520270779600_Monksetal1999","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1085\/jgp.113.3.415","article-title":"Helical structure and packing orientation of the S2 segment in the Shaker K+ channel","volume":"113","author":"Monks","year":"1999","journal-title":"J. Gen. Physiol."},{"key":"2023072520270779600_Morietal1991","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/350398a0","article-title":"Primary structure and functional expression from complementary DNA of a brain calcium channel","volume":"350","author":"Mori","year":"1991","journal-title":"Nature."},{"key":"2023072520270779600_Nonner1979","first-page":"345","article-title":"Effects of Leiurus scorpion venom on the \u201cgating\u201d current in myelinated nerve","volume":"3","author":"Nonner","year":"1979","journal-title":"Adv. Cytopharmacol."},{"key":"2023072520270779600_Norton1991","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1016\/0041-0101(91)90205-6","article-title":"Structure and structure-function relationships of sea anemone proteins that interact with the sodium channel","volume":"29","author":"Norton","year":"1991","journal-title":"Toxicon."},{"key":"2023072520270779600_Pragnelletal1991","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/0014-5793(91)81296-K","article-title":"Cloning and tissue-specific expression of the brain calcium channel beta-subunit","volume":"291","author":"Pragnell","year":"1991","journal-title":"FEBS Lett."},{"key":"2023072520270779600_Reilyetal1995","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1007\/BF00208803","article-title":"The solution structure of omega-Aga-IVB, a P-type calcium channel antagonist from venom of the funnel web spider, Agelenopsis aperta","volume":"5","author":"Reily","year":"1995","journal-title":"J. Biomol. NMR."},{"key":"2023072520270779600_Rogersetal1996","doi-asserted-by":"crossref","first-page":"15950","DOI":"10.1074\/jbc.271.27.15950","article-title":"Molecular determinants of high affinity binding of alpha-scorpion toxin and sea anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel alpha subunit","volume":"271","author":"Rogers","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2023072520270779600_SheetsandHanck1995","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1085\/jgp.106.4.617","article-title":"Voltage-dependent open state inactivation of cardiac sodium channelsgating current studies with anthopleurin-A toxin","volume":"106","author":"Sheets","year":"1995","journal-title":"J. Gen. Physiol."},{"key":"2023072520270779600_Sheetsetal1999","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/S0006-3495(99)76929-8","article-title":"The Na+ channel voltage sensor associated with inactivation is localized to the external charged residues of domain IV, S4","volume":"77","author":"Sheets","year":"1999","journal-title":"Biophys. J."},{"key":"2023072520270779600_Shonetal1994","doi-asserted-by":"crossref","first-page":"11420","DOI":"10.1021\/bi00204a003","article-title":"Delta-conotoxin GmVIA, a novel peptide from the venom of Conus gloriamaris","volume":"33","author":"Shon","year":"1994","journal-title":"Biochemistry."},{"key":"2023072520270779600_StrichartzandWang1986","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1085\/jgp.88.3.413","article-title":"Rapid voltage-dependent dissociation of scorpion alpha-toxins coupled to Na+ channel inactivation in amphibian myelinated nerves","volume":"88","author":"Strichartz","year":"1986","journal-title":"J. Gen. Physiol."},{"key":"2023072520270779600_Swartz1999","first-page":"A150","article-title":"Inhibition of voltage-gated K+ channel gating currents by hanatoxin","volume":"76","author":"Swartz","year":"1999","journal-title":"Biophys. J."},{"key":"2023072520270779600_SwartzandMacKinnon1997a","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/S0896-6273(00)80306-2","article-title":"Hanatoxin modifies the gating of a voltage-dependent K+ channel through multiple binding sites","volume":"18","author":"Swartz","year":"1997","journal-title":"Neuron."},{"key":"2023072520270779600_SwartzandMacKinnon1997b","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/S0896-6273(00)80307-4","article-title":"Mapping the receptor site for hanatoxin, a gating modifier of voltage-dependent K+ channels","volume":"18","author":"Swartz","year":"1997","journal-title":"Neuron."},{"key":"2023072520270779600_Takahashietal2000","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1006\/jmbi.2000.3609","article-title":"Solution structure of hanatoxin 1, a gating modifier of voltage-dependent K+ channelscommon surface features of gating modifier toxins","volume":"297","author":"Takahashi","year":"2000","journal-title":"J. Mol. Biol."},{"key":"2023072520270779600_WangandStrichartz1983","first-page":"519","article-title":"Purification and physiological characterization of neurotoxins from venoms of the scorpions Centruroides sculpturatus and Leiurus quinquestriatus","volume":"23","author":"Wang","year":"1983","journal-title":"Mol. Pharmacol."},{"key":"2023072520270779600_Weietal1991","doi-asserted-by":"crossref","first-page":"21943","DOI":"10.1016\/S0021-9258(18)54728-1","article-title":"Heterologous regulation of the cardiac Ca2+ channel alpha 1 subunit by skeletal muscle beta and gamma subunits. Implications for the structure of cardiac L-type Ca2+ channels","volume":"266","author":"Wei","year":"1991","journal-title":"J. Biol. Chem."},{"key":"2023072520270779600_Widmeretal1989","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1002\/prot.340060403","article-title":"Three-dimensional structure of the neurotoxin ATX Ia from Anemonia sulcata in aqueous solution determined by nuclear magnetic resonance spectroscopy","volume":"6","author":"Widmer","year":"1989","journal-title":"Proteins."},{"key":"2023072520270779600_Yuetal1993","doi-asserted-by":"crossref","first-page":"13123","DOI":"10.1021\/bi00211a022","article-title":"Sequential assignment and structure determination of spider toxin omega-Aga-IVB","volume":"32","author":"Yu","year":"1993","journal-title":"Biochemistry."}],"container-title":["The Journal of General Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jgp\/article-pdf\/116\/5\/637\/1729606\/8186.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jgp\/article-pdf\/116\/5\/637\/1729606\/8186.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T20:28:54Z","timestamp":1690316934000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jgp\/article\/116\/5\/637\/30076\/A-Hot-Spot-for-the-Interaction-of-Gating-Modifier"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,10,16]]},"references-count":51,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2000,11,1]]}},"URL":"https:\/\/doi.org\/10.1085\/jgp.116.5.637","relation":{},"ISSN":["0022-1295","1540-7748"],"issn-type":[{"value":"0022-1295","type":"print"},{"value":"1540-7748","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,10,16]]}}}