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J. Biol. Chem., Vol. 279, Issue 51, 53674-53682, December 17, 2004

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Interaction between Protein Kinase Cµ and the Vanilloid Receptor Type 1^*

Yun Wang¶, Noemi Kedei, Min Wang, Q. Jane Wang||, Anna R. Huppler, Attila Toth, Richard Tran, and Peter M. Blumberg**

From the NCI, National Institutes of Health, Bethesda, Maryland 20892-4255 and the Neuroscience Research Institute, Peking University, Beijing 100083, China

The capsaicin receptor VR1 is a polymodal nociceptor activated by multiple stimuli. It has been reported that protein kinase C plays a role in the sensitization of VR1. Protein kinase D/PKCµ is a member of the protein kinase D serine/threonine kinase family that exhibits structural, enzymological, and regulatory features distinct from those of the PKCs, with which they are related. As part of our effort to optimize conditions for evaluating VR1 pharmacology, we found that treatment of Chinese hamster ovary (CHO) cells heterologously expressing rat VR1 (CHO/rVR1) with butyrate enhanced rVR1 expression and activity. The expression of PKCµ and PKC1, but not of other PKC isoforms, was also enhanced by butyrate treatment, suggesting the possibility that these two isoforms might contribute to the enhanced activity of rVR1. In support of this hypothesis, we found the following. 1) Overexpression of PKCµ enhanced the response of rVR1 to capsaicin and low pH, and expression of a dominant negative variant of PKCµ reduced the response of rVR1. 2) Reduction of endogenous PKCµ using antisense oligonucleotides decreased the response of exogenous rVR1 expressed in CHO cells as well as of endogenous rVR1 in dorsal root ganglion neurons. 3) PKCµ localized to the plasma membrane when overexpressed in CHO/rVR1 cells. 4) PKCµ directly bound to rVR1 expressed in CHO cells as well as to endogenous rVR1 in dorsal root ganglia or to an N-terminal fragment of rVR1, indicating a direct interaction between PKCµ and rVR1. 5) PKCµ directly phosphorylated rVR1 or a longer N-terminal fragment (amino acids 1–118) of rVR1 but not a shorter one (amino acids 1–99). 6) Mutation of S116A in rVR1 blocked both the phosphorylation of rVR1 by PKCµ and the enhancement by PKCµ of the rVR1 response to capsaicin. We conclude that PKCµ functions as a direct modulator of rVR1.

Received for publication, September 8, 2004

^* This work was supported in part by a grant from the National Natural Science Foundation of China (30330026) (to J. S. Han), by a National Basic Research Program of China Grant (G1999054000) (to Y. W.), and by an Outstanding Young Teacher of Higher Academic School Grant 2001-182 (to Y. W.) from the Ministry of Education of China. 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.

^|| Present address: Dept. of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15261.

¶ To whom correspondence may be addressed: Neuroscience Research Institute, Dept. of Neurobiology, Peking University, 38 Xue Yuan Rd., Beijing 100083, China. Tel.: 86-10-828201119; Fax: 86-10-82801111; E-mail: wangy66{at}bjmu.edu.cn. ^** To whom correspondence may be addressed: National Cancer Institute, Bldg. 37, Rm. 4048, 37 Convent Dr., MSC 4255, Bethesda, MD 20892-4255. Tel.: 301-496-3189; Fax: 301-496-8709; E-mail: blumberp{at}dc37a.nci.nih.gov.

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