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The Journal of Neuroscience, May 25, 2005, 25(21):5109-5116; doi:10.1523/JNEUROSCI.0237-05.2005

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Cellular/Molecular
Extracellular Cations Sensitize and Gate Capsaicin Receptor TRPV1 Modulating Pain Signaling

Gerard P. Ahern, Ian M. Brooks, Rosa Linda Miyares, and Xiang-bin Wang

Department of Pharmacology, Georgetown University, Washington, DC 20007

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.

Key words: TRPV1; VR1; nociception; cations; ionic strength; pain

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Received Jan 17, 2005; revised April 14, 2005; accepted April 15, 2005.

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