TRPV1 is a physiological regulator of μ-opioid receptors

Paul C. Scherer, Nicholas W. Zaccor, Neil M. Neumann, Chirag Vasavda, Roxanne K Barrow, Andrew Ewald, Feng Rao, Charlotte Sumner, Solomon H Snyder

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)13561-13566
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number51
DOIs
StatePublished - Dec 19 2017

Fingerprint

Transient Receptor Potential Channels
Opioid Receptors
Opioid Analgesics
GTP-Binding Proteins
Phosphorylation
G-Protein-Coupled Receptor Kinase 5
Calcium
Arrestin
Calmodulin
Respiratory Insufficiency
Cell Membrane

Keywords

  • G protein-coupled receptor kinase 5
  • G protein-coupled receptors
  • Opiates
  • Transient receptor potential vanilloid 1
  • μ-opioid receptor

ASJC Scopus subject areas

  • General

Cite this

TRPV1 is a physiological regulator of μ-opioid receptors. / Scherer, Paul C.; Zaccor, Nicholas W.; Neumann, Neil M.; Vasavda, Chirag; Barrow, Roxanne K; Ewald, Andrew; Rao, Feng; Sumner, Charlotte; Snyder, Solomon H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 51, 19.12.2017, p. 13561-13566.

Research output: Contribution to journalArticle

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