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J. Biol. Chem., Vol. 279, Issue 33, 34553-34561, August 13, 2004

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TRPV1 Acts as Proton Channel to Induce Acidification in Nociceptive Neurons^*

Nicole Hellwig, Tim D. Plant, Wiebke Janson, Michael Schäfer, Günter Schultz, and Michael Schaefer¶

From the Department of Pharmacology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Thielallee 67-73, 14195 Berlin and the Department of Anaesthesiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany

The low extracellular pH of inflamed or ischemic tissues enhances painful sensations by sensitizing and activating the vanilloid receptor 1 (TRPV1). We report here that activation of TRPV1 results in a marked intracellular acidification in nociceptive dorsal root ganglion neurons and in a heterologous expression system. A characterization of the underlying mechanisms revealed a Ca²⁺-dependent intracellular acidification operating at neutral pH and an additional as yet unrecognized direct proton conductance through the poorly selective TRPV1 pore operating in acidic extracellular media. Large organic cations permeate through the activated TRPV1 pore even in the presence of physiological concentrations of Na⁺, Mg²⁺, and Ca²⁺. The wide pore and the unexpectedly high proton permeability of TRPV1 point to a proton hopping permeation mechanism along the water-filled channel pore. In acidic media, the high relative proton permeability through TRPV1 defines a novel proton entry mechanism in nociceptive neurons.

Received for publication, March 17, 2004 , and in revised form, May 28, 2004.

Note Added in Proof—During preparation of the manuscript, a proton conductance of human TRPV1 has been shown by Vulcu et al. (50) upon heterologous expression in Xenopus laevis oocytes.

^* This work was supported by the Fonds der Chemischen Industrie and by the Deutsche Forschungsgemeinschaft (Grants Scha 941/1 and SFB 366). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 49-30-8445-1863; Fax: 49-30-8445-1818; E-mail: schae{at}zedat.fu-berlin.de.

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