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J. Biol. Chem., Vol. 277, Issue 16, 13375-13378, April 19, 2002

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ACCELERATED PUBLICATION
Direct Phosphorylation of Capsaicin Receptor VR1 by Protein Kinase C and Identification of Two Target Serine Residues^*

Mitsuko Numazaki^§, Tomoko Tominaga^¶, Hidenori Toyooka^§, and Makoto Tominaga

From the  Department of Physiology, Mie University School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan, the ^§ Department of Anesthesiology, University of Tsukuba School of Medicine, Tsukuba 305-0006, Japan, and the ^¶ Foundation for Advancement of International Science, Tsukuba 305-0062, Japan

The capsaicin receptor, VR1, is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. It has been reported that ATP, one of the inflammatory mediators, potentiates the VR1 currents evoked by capsaicin or protons and reduces the temperature threshold for activation of VR1 through metabotropic P2Y₁ receptors in a protein Kinase C (PKC)-dependent pathway, suggesting the phosphorylation of VR1 by PKC. In this study, direct phosphorylation of VR1 upon application of phorbol 12-myristate 13-acetate (PMA) was proven biochemically in cells expressing VR1. An in vitro kinase assay using glutathione S-transferase fusion proteins with cytoplasmic segments of VR1 showed that both the first intracellular loop and carboxyl terminus of VR1 were phosphorylated by PKC. Patch clamp analysis of the point mutants where Ser or Thr residues were replaced with Ala in the total 16 putative phosphorylation sites showed that two Ser residues, Ser⁵⁰² and Ser⁸⁰⁰ were involved in the potentiation of the capsaicin-evoked currents by either PMA or ATP. In the cells expressing S502A/S800A double mutant, the temperature threshold for activation was not reduced upon PMA treatment. The two sites would be promising targets for the development of substance modulating VR1 function, thereby reducing pain.

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