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, Peter J. Cabot

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

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 fine-tuning of nociceptive responses that allow for rapid modulation of TRPV1 responses independent of transcriptional changes.

Original languageEnglish (US)
Pages (from-to)19540-19550
Number of pages11
JournalJournal of Biological Chemistry
Volume283
Issue number28
DOIs
StatePublished - Jul 11 2008

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Vetter, I., Cheng, W., Peiris, M., Wyse, B. D., Roberts-Thomson, S. J., Zheng, J., Monteith, G. R., & Cabot, P. J. (2008). Rapid, opioid-sensitive mechanisms involved in transient receptor potential vanilloid 1 sensitization. Journal of Biological Chemistry, 283(28), 19540-19550. https://doi.org/10.1074/jbc.M707865200