Activation of mu opioid receptors sensitizes transient receptor potential vanilloid type 1 (TRPV1) via β-arrestin-2-mediated cross-talk.
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 β-arrestin2 actively participates in a scaffolding mechanism to inhibit TRPV1 phosphorylation, thereby reducing TRPV1 sensitivity. In this study, we evaluated the effect of β-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 β-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 β-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 β-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.
Department of Oral and Maxillofacial Surgery, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
Matthew P
MP
Rowan
Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
Sonya M
SM
Bierbower
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
Michael A
MA
Eskander
Department of Oral and Maxillofacial Surgery, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
Kalina
K
Szteyn
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
Elaine D
ED
Por
Department of Oral and Maxillofacial Surgery, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
Ruben
R
Gomez
Departments of Pharmacology and Medicine, Monash Institute of Pharmacological Sciences, Parkville, Victoria, Australia.
Nicholas
N
Veldhuis
Departments of Pharmacology and Medicine, Monash Institute of Pharmacological Sciences, Parkville, Victoria, Australia.
Nigel W
NW
Bunnett
Department of Oral and Maxillofacial Surgery, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America; Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America; Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
Nathaniel A
NA
Jeske
D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D002478:Cells, Cultured; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer; D005663:Furans / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology; D011753:Pyrones / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000819:agonists*; D050916:TRPV Cation Channels / Q000378:metabolism*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C502982:9-(benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho(2,1-c)pyran-7-carboxylic acid methyl ester; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D005663:Furans; D011753:Pyrones; D017450:Receptors, Opioid, mu; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009020:Morphine