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J. Biol. Chem., Vol. 281, Issue 43, 32879-32890, October 27, 2006

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Cannabinoid WIN 55,212-2 Regulates TRPV1 Phosphorylation in Sensory Neurons^*

Nathaniel A. Jeske, Amol M. Patwardhan, Nikita Gamper^¶1, Theodore J. Price², Armen N. Akopian, and Kenneth M. Hargreaves³

From the Departments of Endodontics, Pharmacology, and ^¶Physiology, University of Texas Health Science Center, San Antonio, Texas 78229-3900

Cannabinoids are known to have multiple sites of action in the nociceptive system, leading to reduced pain sensation. However, the peripheral mechanism(s) by which this phenomenon occurs remains an issue that has yet to be resolved. Because phosphorylation of TRPV1 (transient receptor potential subtype V1) plays a key role in the induction of thermal hyperalgesia in inflammatory pain models, we evaluated whether the cannabinoid agonist WIN 55,212-2 (WIN) regulates the phosphorylation state of TRPV1. Here, we show that treatment of primary rat trigeminal ganglion cultures with WIN led to dephosphorylation of TRPV1, specifically at threonine residues. Utilizing Chinese hamster ovary cell lines, we demonstrate that Thr¹⁴⁴ and Thr³⁷⁰ were dephosphorylated, leading to desensitization of the TRPV1 receptor. This post-translational modification occurred through activation of the phosphatase calcineurin (protein phosphatase 2B) following WIN treatment. Furthermore, knockdown of TRPA1 (transient receptor potential subtype A1) expression in sensory neurons by specific small interfering RNA abolished the WIN effect on TRPV1 dephosphorylation, suggesting that WIN acts through TRPA1. We also confirm the importance of TRPA1 in WIN-induced dephosphorylation of TRPV1 in Chinese hamster ovary cells through targeted expression of one or both receptor channels. These results imply that the cannabinoid WIN modulates the sensitivity of sensory neurons to TRPV1 activation by altering receptor phosphorylation. In addition, our data could serve as a useful strategy in determining the potential use of certain cannabinoids as peripheral analgesics.

Received for publication, April 5, 2006 , and in revised form, August 31, 2006.

^* This work was supported by National Institutes of Health Grants F32-DE016500 (to N. A. J.), R21-DE014928 (to A. N. A.), and R01-DA19585 (to K. M. H.). 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 Present address: Inst. of Membrane and System Biology, University of Leeds, Leeds LS2 9JT, UK.

² Present address: Dept. of Anesthesia, McGill University, Montreal, Quebec H3G 1Y6, Canada.

³ To whom correspondence should be addressed: Dept. of Endodontics, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. Tel.: 210-567-3388; Fax: 210-567-3389; E-mail: Hargreaves{at}UTHSCSA.edu.

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