Jendryke, Thomas and Prochazkova, Michaela and Hall, Bradford E. and Nordmann, Gregory C. and Schladt, Moritz and Milenkovic, Vladimir M. and Kulkarni, Ashok B. and Wetzel, Christian H. (2016) TRPV1 function is modulated by Cdk5-mediated phosphorylation: insights into the molecular mechanism of nociception. SCIENTIFIC REPORTS, 6: 22007. ISSN 2045-2322,
Full text not available from this repository. (Request a copy)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 rTRPV1(T406) 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 Ca2+-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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-KINASE-C; CAPSAICIN RECEPTOR VR1; RAT SENSORY NEURONS; POTENTIAL VANILLOID-1; SINGLE-CHANNEL; ION-CHANNEL; HEAT; PAIN; DESENSITIZATION; ACTIVATION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Psychiatrie und Psychotherapie > Molekulare Neurowissenscahften |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Mar 2019 08:10 |
| Last Modified: | 12 Mar 2019 08:10 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2392 |
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