title: TRPV1 function is modulated by Cdk5-mediated phosphorylation: insights into the molecular mechanism of nociception.
abstract: TRPV1 is a polymodally activated cation channel acting as key receptor in nociceptive neurons. Its function is strongly affected by kinase-mediated phosphorylation leading to hyperalgesia and allodynia. We present behavioral and molecular data indicating that TRPV1 is strongly modulated by Cdk5-mediated phosphorylation at position threonine-407(mouse)/T406(rat). Increasing or decreasing Cdk5 activity in genetically engineered mice has severe consequences on TRPV1-mediated pain perception leading to altered capsaicin consumption and sensitivity to heat. To understand the molecular and structural/functional consequences of TRPV1 phosphorylation, we generated various rTRPV1T406 receptor variants to mimic phosphorylated or dephosphorylated receptor protein. We performed detailed functional characterization by means of electrophysiological whole-cell and single-channel recordings as well as Ca(2+)-imaging and challenged recombinant rTRPV1 receptors with capsaicin, low pH, or heat. We found that position T406 is critical for the function of TRPV1 by modulating ligand-sensitivity, activation, and desensitization kinetics as well as voltage-dependence. Based on high resolution structures of TRPV1, we discuss T406 being involved in the molecular transition pathway, its phosphorylation leading to a conformational change and influencing the gating of the receptor. Cdk5-mediated phosphorylation of T406 can be regarded as an important molecular switch modulating TRPV1-related behavior and pain sensitivity.
authors.affiliation: Molecular Neurosciences, Department of Psychiatry and Psychotherapy, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jendryke
authors.affiliation: Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Michaela
authors.initials: M
authors.lastname: Prochazkova
authors.affiliation: Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Bradford E
authors.initials: BE
authors.lastname: Hall
authors.affiliation: Molecular Neurosciences, Department of Psychiatry and Psychotherapy, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Grégory C
authors.initials: GC
authors.lastname: Nordmann
authors.affiliation: Molecular Neurosciences, Department of Psychiatry and Psychotherapy, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Schladt
authors.affiliation: Molecular Neurosciences, Department of Psychiatry and Psychotherapy, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Vladimir M
authors.initials: VM
authors.lastname: Milenkovic
authors.affiliation: Functional Genomics Section, Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ashok B
authors.initials: AB
authors.lastname: Kulkarni
authors.affiliation: Molecular Neurosciences, Department of Psychiatry and Psychotherapy, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Christian H
authors.initials: CH
authors.lastname: Wetzel
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D003216:Conditioning, Operant / Q000502:physiology*; D003412:Cricetulus; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics* / Q000378:metabolism; D004326:Drinking; D015870:Gene Expression; D057809:HEK293 Cells; D006358:Hot Temperature; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D059225:Nociception / Q000502:physiology*; D017288:Pain Threshold / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D051381:Rats; D050916:TRPV Cation Channels / Q000235:genetics* / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000378:metabolism
chemical_list: D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D002211:Capsaicin; D002118:Calcium