title: Phosphorylation of TRPV1 by cyclin-dependent kinase 5 promotes TRPV1 surface localization, leading to inflammatory thermal hyperalgesia.
abstract: Cyclin-dependent kinase 5 (Cdk5) is an important serine/threonine kinase that plays critical roles in many physiological processes. Recently, Cdk5 has been reported to phosphorylate TRPV1 at threonine 407 (Thr-407) in humans (Thr-406 in rats), which enhances the function of TRPV1 channel and promotes thermal hyperalgesia in the complete Freund's adjuvant (CFA)-induced inflammatory pain rats. However, the underlying mechanisms are still unknown. Here, we demonstrate that Cdk5 phosphorylates TRPV1 at Threonine 406 and promotes the surface localization of TRPV1, leading to inflammatory thermal hyperalgesia. The mutation of Thr-406 of TRPV1 to alanine reduced the interaction of TRPV1 with the cytoskeletal elements and decreased the binding of TRPV1 with the motor protein KIF13B, which led to reduced surface distribution of TRPV1. Disrupting the phosphorylation of TRPV1 at Thr-406 dramatically reduced the surface level of TRPV1 in HEK 293 cells after transient expression and the channel function in cultured dorsal root ganglion (DRG) neurons. Notably, intrathecal administration of the interfering peptide against the phosphorylation of Thr-406 alleviated heat hyperalgesia and reduced the surface level of TRPV1 in inflammatory pain rats. Together, these results demonstrate that Cdk5-mediated phosphorylation of TRPV1 at Thr-406 increases the surface level and the function of TRPV1, while the TAT-T406 peptide can effectively attenuate thermal hyperalgesia. Our studies provide a potential therapy for inflammatory pain.
authors.affiliation: Neuroscience Research Institute and Department of Neurobiology,The Key Laboratory for Neuroscience of the Ministry of Education/National Health and Family Planning Commission, School of Basic Medical Sciences,Peking University Health Science Center,Beijing100191,China; PKU-IDG/McGovern Institute for Brain Research,Peking University,Beijing100871,China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Chemical Engineering and Biotechnology,Xingtai University,Xingtai054001,Hebei Province,China.
authors.forename: Junxie
authors.initials: J
authors.lastname: Du
authors.affiliation: Key Laboratory of Molecular and Developmental Biology,Institute of Genetics and Developmental Biology,Chinese Academy of Sciences,Beijing100101,China.
authors.forename: Yanrui
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Neuroscience Research Institute and Department of Neurobiology,The Key Laboratory for Neuroscience of the Ministry of Education/National Health and Family Planning Commission, School of Basic Medical Sciences,Peking University Health Science Center,Beijing100191,China; PKU-IDG/McGovern Institute for Brain Research,Peking University,Beijing100871,China. Electronic address: wangy66@bjmu.edu.cn.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000409:Alanine / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000633:toxicity; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D006930:Hyperalgesia / Q000209:etiology*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications*; D016547:Kinesins; D008297:Male; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000627:therapeutic use; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D013912:Threonine / Q000235:genetics / Q000378:metabolism
chemical_list: C492235:Cdk5r1 protein, rat; D010455:Peptides; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D013912:Threonine; D005620:Freund's Adjuvant; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C504977:KIF13B protein, rat; D016547:Kinesins; D000409:Alanine; D002118:Calcium
keywords: Cdk5; Hyperalgesia; Membrane trafficking; Phosphorylation; TRPV1