title: Extracellular cations sensitize and gate capsaicin receptor TRPV1 modulating pain signaling.
abstract: Transient receptor potential (TRP) channels detect diverse sensory stimuli, including alterations in osmolarity. However, a molecular detector of noxious hypertonic stimuli has not yet been identified. We show here that acute pain-related behavior evoked by elevated ionic strength is abolished in TRP vanilloid subtype 1 (TRPV1)-null mice and inhibited by iodoresiniferatoxin, a potent TRPV1 antagonist. Electrophysiological recordings demonstrate a novel form of ion channel modulation by which extracellular Na+, Mg2+, and Ca2+ ions sensitize and activate the capsaicin receptor, TRPV1. At room temperature, increasing extracellular Mg2+ (from 1 to 5 mM) or Na+ (+50 mM) increased ligand-activated currents up to fourfold, and 10 mM Mg2+ reduced the EC50 for activation by capsaicin from 890 to 450 nM. Moreover, concentrations of divalent cations >10 mM directly gate the receptor. These effects occur via electrostatic interactions with two glutamates (E600 and E648) formerly identified as proton-binding residues. Furthermore, phospholipase C-mediated signaling enhances the effects of cations, and physiological concentrations of cations contribute to the bradykinin-evoked activation of TRPV1 and the sensitization of the receptor to heat. Thus, the modulation of TRPV1 by cationic strength may contribute to inflammatory pain signaling.
authors.affiliation: Department of Pharmacology, Georgetown University, Washington, DC 20007, USA. gpa3@georgetown.edu
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Ahern
authors.forename: Ian M
authors.initials: IM
authors.lastname: Brooks
authors.forename: Rosa Linda
authors.initials: RL
authors.lastname: Miyares
authors.forename: Xiang-bin
authors.initials: XB
authors.lastname: Wang
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000613:Aminobutyrates; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001522:Behavior, Animal / Q000502:physiology; D001920:Bradykinin; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers; D002211:Capsaicin / Q000494:pharmacology; D002412:Cations / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D063388:Endocannabinoids; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008278:Magnesium Sulfate / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008845:Microinjections; D008954:Models, Biological; D016296:Mutagenesis; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009620:Nodose Ganglion / Q000166:cytology; D009865:Oocytes; D010146:Pain / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D018408:Patch-Clamp Techniques / Q000379:methods; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D011493:Protein Kinase C; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D050916:TRPV Cation Channels / Q000172:deficiency / Q000502:physiology*; D013696:Temperature; D013997:Time Factors; D014162:Transfection / Q000379:methods
chemical_list: D000613:Aminobutyrates; D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D002412:Cations; D063388:Endocannabinoids; C401954:N(gamma)-acetyl-2,4-diaminobutyric acid; D053284:Polyunsaturated Alkamides; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D015240:Phorbol 12,13-Dibutyrate; D008278:Magnesium Sulfate; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D002211:Capsaicin; D001920:Bradykinin; D002118:Calcium; C078814:anandamide