HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 14, 9377-9387, April 4, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/14/9377    most recent M709377200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ohta, T. Articles by Ito, S. Search for Related Content PubMed PubMed Citation Articles by Ohta, T. Articles by Ito, S. Social Bookmarking                      What's this?

Novel Gating and Sensitizing Mechanism of Capsaicin Receptor (TRPV1)

TONIC INHIBITORY REGULATION OF EXTRACELLULAR SODIUM THROUGH THE EXTERNAL PROTONATION SITES ON TRPV1^*

Toshio Ohta¹, Toshiaki Imagawa, and Shigeo Ito

From the Laboratory of Pharmacology, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan and Biological Chemistry, Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan

Transient receptor potential V1 (TRPV1) is a nonselective cation channel expressed in nociceptors and activated by capsaicin. TRPV1 detects diverse stimuli, including acid, heat, and endogenous vanilloids, and functions as a molecular integrator of pain perception. Herein we demonstrate a novel regulatory role of extracellular Na⁺ ([Na⁺]_o) on TRPV1 function. In human embryonic kidney 293 cells expressing porcine TRPV1, low [Na⁺]_o evoked increases of [Ca²⁺]_i that were suppressed by TRPV1 antagonists and facilitated responses to capsaicin, protons, heat, and an endovanilloid. [Na⁺]_o removal simultaneously elicited a [Ca²⁺]_i increase and outward-rectified current with a reversal potential similar to those of capsaicin. Neutralization of the two acidic residues which confer the proton sensitivity to TRPV1 resulted in a reduction of low [Na⁺]_o-induced responses. In primary culture of porcine sensory neurons, the removal of [Na⁺]_o produced a [Ca²⁺]_i increase and current responses only in the cells responding to capsaicin. Low [Na⁺]_o evoked a [Ca²⁺]_i increase in sensory neurons of wild type mice, but not TRPV1-null mice, and in human embryonic kidney 293 cells expressing human TRPV1. The present results suggest that [Na⁺]_o negatively regulates the gating and polymodal sensitization of the TRPV1 channel. [Na⁺]_o surrounding several proton-sensitive sites on the extracellular side of the pore-forming loop of the TRPV1 channel may play an important role as a brake to suppress the excessive activity of this channel under physiological conditions.

Received for publication, November 15, 2007 , and in revised form, January 7, 2008.

^* This work was supported by grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed: N18W9, Laboratory of Pharmacology, Dept. of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan. Fax: 81-11-706-5220; E-mail: tohta{at}vetmed.hokudai.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				T. Ohta, T. Imagawa, and S. Ito Involvement of Transient Receptor Potential Vanilloid Subtype 1 in Analgesic Action of Methylsalicylate Mol. Pharmacol., February 1, 2009; 75(2): 307 - 317. [Abstract] [Full Text] [PDF]