cAMP-dependent protein kinase regulates desensitization of the capsaicin receptor (VR1) by direct phosphorylation

Neuron. 2002 Aug 15;35(4):721-31. doi: 10.1016/s0896-6273(02)00802-4.

Abstract

The capsaicin receptor, VR1 (also known as TRPV1), is a ligand-gated ion channel expressed on nociceptive sensory neurons that responds to noxious thermal and chemical stimuli. Capsaicin responses in sensory neurons exhibit robust potentiation by cAMP-dependent protein kinase (PKA). In this study, we demonstrate that PKA reduces VR1 desensitization and directly phosphorylates VR1. In vitro phosphorylation, phosphopeptide mapping, and protein sequencing of VR1 cytoplasmic domains delineate several candidate PKA phosphorylation sites. Electrophysiological analysis of phosphorylation site mutants clearly pinpoints Ser116 as the residue responsible for PKA-dependent modulation of VR1. Given the significant roles of VR1 and PKA in inflammatory pain hypersensitivity, VR1 phosphorylation at Ser116 by PKA may represent an important molecular mechanism involved in the regulation of VR1 function after tissue injury.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence / genetics
  • Animals
  • Binding Sites / drug effects
  • Binding Sites / genetics
  • CHO Cells
  • COS Cells
  • Capsaicin / pharmacology
  • Central Nervous System / enzymology*
  • Cricetinae
  • Cyclic AMP / analogs & derivatives
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / drug effects
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Mutation / drug effects
  • Mutation / genetics
  • Neurons, Afferent / drug effects
  • Neurons, Afferent / enzymology*
  • Nociceptors / drug effects
  • Nociceptors / enzymology*
  • Pain / enzymology*
  • Pain / genetics
  • Phosphorylation / drug effects
  • Protein Structure, Tertiary / drug effects
  • Protein Structure, Tertiary / genetics
  • Receptors, Drug / drug effects
  • Receptors, Drug / genetics
  • Receptors, Drug / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Serine / genetics
  • Serine / metabolism
  • Transfection

Substances

  • Receptors, Drug
  • Recombinant Fusion Proteins
  • Serine
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Capsaicin