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dc.contributor.authorHall, B.E.
dc.contributor.authorProchazkova, M.
dc.contributor.authorSapio, M.R.
dc.date.accessioned2019-06-21T18:46:24Z
dc.date.available2019-06-21T18:46:24Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85040809695&doi=10.1038%2fs41598-018-19532-6&partnerID=40&md5=93feeb00cb1416fe4f2b8c954f7b8610
dc.identifier.urihttp://hdl.handle.net/10713/9669
dc.description.abstractCyclin-dependent kinase 5 (Cdk5) is a key neuronal kinase that is upregulated during inflammation, and can subsequently modulate sensitivity to nociceptive stimuli. We conducted an in silico screen for Cdk5 phosphorylation sites within proteins whose expression was enriched in nociceptors and identified the chemo-responsive ion channel Transient Receptor Potential Ankyrin 1 (TRPA1) as a possible Cdk5 substrate. Immunoprecipitated full length TRPA1 was shown to be phosphorylated by Cdk5 and this interaction was blocked by TFP5, an inhibitor that prevents activation of Cdk5. In vitro peptide-based kinase assay revealed that four of six TRPA1 Cdk5 consensus sites acted as substrates for Cdk5, and modeling of the ankyrin repeats disclosed that phosphorylation would occur at characteristic pockets within the (T/S)PLH motifs. Calcium imaging of trigeminal ganglion neurons from genetically engineered mice overexpressing or lacking the Cdk5 activator p35 displayed increased or decreased responsiveness, respectively, to stimulation with the TRPA1 agonist allylisothiocyanate (AITC). AITC-induced chemo-nociceptive behavior was also heightened in vivo in mice overexpressing p35 while being reduced in p35 knockout mice. Our findings demonstrate that TRPA1 is a substrate of Cdk5 and that Cdk5 activity is also able to modulate TRPA1 agonist-induced calcium influx and chemo-nociceptive behavioral responses. Copyright 2018 The Author(s).en_US
dc.description.urihttps://dx.doi.org/10.1038/s41598-018-19532-6en_US
dc.language.isoen-USen_US
dc.publisherNature Publishing Groupen_US
dc.relation.ispartofScientific Reports
dc.subject.meshCyclin-Dependent Kinase 5--immunologyen_US
dc.subject.meshNociceptionen_US
dc.subject.meshPhosphorylationen_US
dc.subject.meshTRPA1 Cation Channelen_US
dc.titlePhosphorylation of the Transient Receptor Potential Ankyrin 1 by Cyclin-dependent Kinase 5 affects Chemo-nociceptionen_US
dc.typeArticleen_US
dc.identifier.doi10.1038/s41598-018-19532-6
dc.identifier.pmid29352128


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