Cyclin-dependent kinase 5 modulates nociceptive signaling through direct phosphorylation of transient receptor potential vanilloid 1.
Transient receptor potential vanilloid 1 (TRPV1), a ligand-gated cation channel highly expressed in small-diameter sensory neurons, is activated by heat, protons, and capsaicin. The phosphorylation of TRPV1 provides a versatile regulation of intracellular calcium levels and is critical for TRPV1 function in responding to a pain stimulus. We have previously reported that cyclin-dependent kinase 5 (Cdk5) activity regulates nociceptive signaling. In this article we report that the Cdk5-mediated phosphorylation of TRPV1 at threonine-407 can modulate agonist-induced calcium influx. Inhibition of Cdk5 activity in cultured dorsal root ganglia neurons resulted in a significant reduction of TRPV1-mediated calcium influx, and this effect could be reversed by restoring Cdk5 activity. Primary nociceptor-specific Cdk5 conditional-knockout mice showed reduced TRPV1 phosphorylation, resulting in significant hypoalgesia. Thus, the present study indicates that Cdk5-mediated TRPV1 phosphorylation is important in the regulation of pain signaling.
Pareek
Tej K
TK
Functional Genomics Section, Craniofacial Developmental Biology and Regeneration Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Keller
Jason
J
Kesavapany
Sashi
S
Agarwal
Nitin
N
Kuner
Rohini
R
Pant
Harish C
HC
Iadarola
Michael J
MJ
Brady
Roscoe O
RO
Kulkarni
Ashok B
AB
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D020013:Calcium Signaling; D051360:Cyclin-Dependent Kinase 5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005727:Ganglia, Spinal / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009619:Nociceptors / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D050916:TRPV Cation Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013912:Threonine / Q000737:chemistry
D017931:DNA Primers; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D013912:Threonine; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse