Activation of mu opioid receptors sensitizes Transient Receptor Potential Vanilloid Type 1 (TRPV1) via beta-arrestin-2-mediated cross-talk

Matthew P Rowan, Sonya M Bierbower, Michael A Eskander, Kalina Szteyn, Elaine D Por, Ruben Gomez, Nicholas Andrew Veldhuis, Nigel William Bunnett, Nathaniel A Jeske

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The transient receptor potential family V1 channel (TRPV1) is activated by multiple stimuli, including capsaicin, acid, endovanilloids, and heat (>42C). Post-translational modifications to TRPV1 result in dynamic changes to the sensitivity of receptor activation. We have previously demonstrated that ?-arrestin2 actively participates in a scaffolding mechanism to inhibit TRPV1 phosphorylation, thereby reducing TRPV1 sensitivity. In this study, we evaluated the effect of ?-arrestin2 sequestration by G-protein coupled receptors (GPCRs) on thermal and chemical activation of TRPV1. Here we report that activation of mu opioid receptor by either morphine or DAMGO results in ?-arrestin2 recruitment to mu opioid receptor in sensory neurons, while activation by herkinorin does not. Furthermore, treatment of sensory neurons with morphine or DAMGO stimulates ?-arrestin2 dissociation from TRPV1 and increased sensitivity of the receptor. Conversely, herkinorin treatment has no effect on TRPV1 sensitivity. Additional behavioral studies indicate that GPCR-driven ?-arrestin2 sequestration plays an important peripheral role in the development of thermal sensitivity. Taken together, the reported data identify a novel cross-talk mechanism between GPCRs and TRPV1 that may contribute to multiple clinical conditions.
Original languageEnglish
Article numbere93688
Number of pages12
JournalPLoS ONE
Issue number4
Publication statusPublished - 2014

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