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J. Biol. Chem., Vol. 283, Issue 10, 6162-6174, March 7, 2008

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Calcium Plays a Central Role in the Sensitization of TRPV3 Channel to Repetitive Stimulations^*

Rui Xiao, Jisen Tang¹, Chunbo Wang, Craig K. Colton², Jinbin Tian, and Michael X. Zhu³

From the Department of Neuroscience and Center for Molecular Neurobiology, Biophysics Graduate Program, Ohio State University, Columbus, Ohio 43210

Transient receptor potential channels are involved in sensing chemical and physical changes inside and outside of cells. TRPV3 is highly expressed in skin keratinocytes, where it forms a nonselective cation channel activated by hot temperatures in the innocuous and noxious range. The channel has also been implicated in flavor sensation in oral and nasal cavities as well as being a molecular target of some allergens and skin sensitizers. TRPV3 is unique in that its activity is sensitized upon repetitive stimulations. Here we investigated the role of calcium ions in the sensitization of TRPV3 to repetitive stimulations. We show that the sensitization is accompanied by a decrease of Ca²⁺-dependent channel inhibition mediated by calmodulin acting at an N-terminal site (amino acids 108–130) and by an acidic residue (Asp⁶⁴¹) at the pore loop of TRPV3. These sites also contribute to the voltage dependence of TRPV3. During sensitization, the channel displayed a gradual shift of the voltage dependence to more negative potentials as well as uncoupling from voltage sensing. The initial response to ligand stimulation was increased and sensitization to repetitive stimulations was decreased by increasing the intracellular Ca²⁺-buffering strength, inhibiting calmodulin, or disrupting the calmodulin-binding site. Mutation of Asp⁶⁴¹ to Asn abolished the high affinity extracellular Ca²⁺-mediated inhibition and greatly facilitated the activation of TRPV3. We conclude that Ca²⁺ inhibits TRPV3 from both the extracellular and intracellular sides. The inhibition is sequentially reduced, appearing as sensitization to repetitive stimulations.

Received for publication, August 7, 2007 , and in revised form, January 2, 2008.

^* This work was supported by National Institutes of Health Grants R01-NS042183 and R21-NS056942 (to M. X. Z.), National Institutes of Health Grant P30-NS045758, and American Heart Association Grant-in-aid 0755277B. 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.

¹ Postdoctoral fellowship recipient of American Heart Association Ohio Valley Affiliate.

² Recipient of the Meier Schlesinger graduate fellowship.

³ To whom correspondence should be addressed: Center for Molecular Neurobiology, Ohio State University, 168 Rightmire Hall, 1060 Carmack Rd., Columbus, OH 43210. Tel.: 614-292-8173; Fax: 614-292-5379; E-mail: zhu.55{at}osu.edu.

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