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J. Biol. Chem., Vol. 283, Issue 28, 19540-19550, July 11, 2008

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Rapid, Opioid-sensitive Mechanisms Involved in Transient Receptor Potential Vanilloid 1 Sensitization^*

Irina Vetter, Wei Cheng, Madusha Peiris, Bruce D. Wyse, Sarah J. Roberts-Thomson, Jie Zheng, Gregory R. Monteith, and Peter J. Cabot¹

From the School of Pharmacy, The University of Queensland, St Lucia, Queensland 4072, Australia and the Department of Physiology and Membrane Biology, School of Medicine, The University of California, Davis, California 95616

TRPV1 is a nociceptive, Ca²⁺-selective ion channel involved in the development of several painful conditions. Sensitization of TRPV1 responses by cAMP-dependent PKA crucially contributes to the development of inflammatory hyperalgesia. However, the pathways involved in potentiation of TRPV1 responses by cAMP-dependent PKA remain largely unknown. Using HEK cells stably expressing TRPV1 and the µ opioid receptor, we demonstrated that treatment with the adenylate cyclase activator forskolin significantly increased the multimeric TRPV1 species. Pretreatment with the µ opioid receptor agonist morphine reversed this increased TRPV1 multimerization. FRET analysis revealed that treatment with forskolin did not cause multimerization of pre-existing TRPV1 monomers on the plasma membrane and that intracellular pools of TRPV1 exist mostly as monomers in this model. This suggests that increased TRPV1 multimerization occurred from an intracellular store of inactive TRPV1 monomers. Treatment with forskolin also caused an increase in TRPV1 expression on the plasma membrane not resulting from increased TRPV1 expression, and this rapid TRPV1 translocation was inhibited by treatment with morphine. Thus, potentiation of TRPV1 responses by cAMP-dependent PKA involves plasma membrane insertion of functional TRPV1 multimers formed from an intracellular store of inactive TRPV1 monomers. This potentiation occurs rapidly and can be dynamically modulated by activation of the µ opioid receptor under conditions where cAMP levels are raised, such as with inflammation. Increased translocation and multimerization of TRPV1 channels provide a cellular mechanism for finetuning of nociceptive responses that allow for rapid modulation of TRPV1 responses independent of transcriptional changes.

Received for publication, September 20, 2007 , and in revised form, May 8, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant REY016754A. This work was also supported by an NHMRC Dora Lush Biomedical Research Scholarship (to I. V.) and the American Heart Association (0665201Y) (to J. Z.). 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 Figs. S1–S5.

¹ To whom correspondence should be addressed: School of Pharmacy, The University of Queensland, St Lucia 4072, Australia. Tel.: 61-7-3365-1376; Fax: 61-7-3365-1688; E-mail: p.cabot{at}uq.edu.au.

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