The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

2014 ◽  
Vol 67 (1) ◽  
pp. 36-73 ◽  
Author(s):  
Nicholas A. Veldhuis ◽  
Daniel P. Poole ◽  
Megan Grace ◽  
Peter McIntyre ◽  
Nigel W. Bunnett
Keyword(s):  
G Protein ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
G Protein Coupled Receptor ◽  
Channel Axis ◽  
Transient Receptor ◽  
G Protein Coupled

scholarly journals TRPV1 is a physiological regulator of μ-opioid receptors

2017 ◽  
Vol 114 (51) ◽  
pp. 13561-13566 ◽  
Author(s):  
Paul C. Scherer ◽  
Nicholas W. Zaccor ◽  
Neil M. Neumann ◽  
Chirag Vasavda ◽  
Roxanne Barrow ◽  
...  
Keyword(s):  
G Protein ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Calcium Calmodulin Dependent ◽  
Potential Strategy ◽  
Transient Receptor

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.

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