TRPV1 is a physiological regulator of μ-opioid receptors

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


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.

MeSH terms

  • Cell Membrane / metabolism
  • G-Protein-Coupled Receptor Kinase 5 / metabolism
  • GTP-Binding Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Phosphorylation
  • Protein Binding
  • Protein Processing, Post-Translational
  • Protein Transport
  • Receptors, Opioid, mu / metabolism*
  • TRPV Cation Channels / metabolism*


  • OPRM1 protein, human
  • Receptors, Opioid, mu
  • TRPV Cation Channels
  • TRPV1 protein, human
  • G-Protein-Coupled Receptor Kinase 5
  • GRK5 protein, human
  • GTP-Binding Proteins