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Proc Natl Acad Sci U S A. 2017 Dec 19;114(51):13561-13566. doi: 10.1073/pnas.1717005114. Epub 2017 Dec 4.

TRPV1 is a physiological regulator of μ-opioid receptors.

Author information

1
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
2
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
3
Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, China 518055.
4
Department of Neurology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
5
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205; ssnyder@jhmi.edu.
6
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
7
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205.

Abstract

Opioids are powerful analgesics, but also carry significant side effects and abuse potential. Here we describe a modulator of the μ-opioid receptor (MOR1), the transient receptor potential channel subfamily vanilloid member 1 (TRPV1). We show that TRPV1 binds MOR1 and blocks opioid-dependent phosphorylation of MOR1 while leaving G protein signaling intact. Phosphorylation of MOR1 initiates recruitment and activation of the β-arrestin pathway, which is responsible for numerous opioid-induced adverse effects, including the development of tolerance and respiratory depression. Phosphorylation stands in contrast to G protein signaling, which is responsible for the analgesic effect of opioids. Calcium influx through TRPV1 causes a calcium/calmodulin-dependent translocation of G protein-coupled receptor kinase 5 (GRK5) away from the plasma membrane, thereby blocking its ability to phosphorylate MOR1. Using TRPV1 to block phosphorylation of MOR1 without affecting G protein signaling is a potential strategy to improve the therapeutic profile of opioids.

KEYWORDS:

G protein-coupled receptor kinase 5; G protein-coupled receptors; opiates; transient receptor potential vanilloid 1; μ-opioid receptor

PMID:
29203659
PMCID:
PMC5754810
DOI:
10.1073/pnas.1717005114
[Indexed for MEDLINE]
Free PMC Article

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