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J. Biol. Chem., Vol. 283, Issue 46, 31274-31278, November 14, 2008

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Tunable Calcium Current through TRPV1 Receptor Channels^*

Damien S. K. Samways¹, Baljit S. Khakh, and Terrance M. Egan

From the Department of Pharmacological and Physiological Science, and The Center for Excellence in Neuroscience, Saint Louis University School of Medicine, St. Louis, Missouri, 63104 and the Departments of Physiology and Neurobiology, UCLA, David Geffen School of Medicine, Los Angeles, California 90095

TRPV1 receptors are polymodal cation channels that open in response to diverse stimuli including noxious heat, capsaicin, and protons. Because Ca²⁺ is vital for TRPV1 signaling, we sought to precisely measure its contribution to TRPV1 responses and discovered that the Ca²⁺ current was tuned by the mode of activation. Using patch clamp photometry, we found that the fraction of the total current carried by Ca²⁺ (called the Pf%) was significantly smaller for TRPV1 currents evoked by protons than for those evoked by capsaicin. Using site-directed mutagenesis, we discovered that the smaller Pf% was due to protonation of three acidic amino acids (Asp⁶⁴⁶, Glu⁶⁴⁸, and Glu⁶⁵¹) that are located in the mouth of the pore. Thus, in keeping with recent reports of time-dependent changes in the ionic permeability of some ligand-gated ion channels, we now show for the first time that the physiologically important Ca²⁺ current of the TRPV1 receptor is also dynamic and depends on the mode of activation. This current is significantly smaller when the receptor is activated by a change in pH, owing to atomic scale interactions of H⁺ and Ca²⁺ with the fixed negative charge of side chains in the pore.

Received for publication, June 25, 2008 , and in revised form, September 4, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health grants (to T. M. E. and B. S. K.). 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 text and three supplemental figures.

¹ To whom correspondence should be addressed: Dept. of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Blvd., St. Louis, MO 63104. Tel.: 314-977-6429; Fax: 314-977-6411; E-mail: samwaysds{at}slu.edu.

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