{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T12:43:01Z","timestamp":1792413781333,"version":"4.4.0"},"reference-count":49,"publisher":"Society for Neuroscience","issue":"21","license":[{"start":{"date-parts":[[2005,11,25]],"date-time":"2005-11-25T00:00:00Z","timestamp":1132876800000},"content-version":"vor","delay-in-days":184,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2005,5,25]]},"abstract":"<jats:p>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<jats:sup>+<\/jats:sup>, Mg<jats:sup>2+<\/jats:sup>, and Ca<jats:sup>2+<\/jats:sup>ions sensitize and activate the capsaicin receptor, TRPV1. At room temperature, increasing extracellular Mg<jats:sup>2+<\/jats:sup>(from 1 to 5 m<jats:sc>m<\/jats:sc>) or Na<jats:sup>+<\/jats:sup>(+50 m<jats:sc>m<\/jats:sc>) increased ligand-activated currents up to fourfold, and 10 m<jats:sc>m<\/jats:sc>Mg<jats:sup>2+<\/jats:sup>reduced the EC<jats:sub>50<\/jats:sub>for activation by capsaicin from 890 to 450 n<jats:sc>m<\/jats:sc>. Moreover, concentrations of divalent cations &gt;10 m<jats:sc>m<\/jats:sc>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.<\/jats:p>","DOI":"10.1523\/jneurosci.0237-05.2005","type":"journal-article","created":{"date-parts":[[2005,5,25]],"date-time":"2005-05-25T21:23:52Z","timestamp":1117056232000},"page":"5109-5116","source":"Crossref","is-referenced-by-count":163,"title":["Extracellular Cations Sensitize and Gate Capsaicin Receptor TRPV1 Modulating Pain Signaling"],"prefix":"10.1523","volume":"25","author":[{"given":"Gerard P.","family":"Ahern","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian M.","family":"Brooks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa 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