cAMP-dependent protein kinase regulates desensitization of the capsaicin receptor (VR1) by direct phosphorylation.
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.
Bhave
Gautam
G
Division of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Zhu
Weiguo
W
Wang
Haibin
H
Brasier
D J
DJ
Oxford
Gerry S
GS
Gereau
Robert W
RW
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D016466:CHO Cells; D019556:COS Cells; D002211:Capsaicin / Q000494:pharmacology; D002490:Central Nervous System / Q000201:enzymology*; D006224:Cricetinae; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D009475:Neurons, Afferent / Q000187:drug effects / Q000201:enzymology*; D009619:Nociceptors / Q000187:drug effects / Q000201:enzymology*; D010146:Pain / Q000201:enzymology* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000235:genetics; D011955:Receptors, Drug / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012694:Serine / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D011955:Receptors, Drug; D011993:Recombinant Fusion Proteins; D012694:Serine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D002211:Capsaicin