title: Activity-dependent phosphorylation of neuronal Kv2.1 potassium channels by CDK5.
abstract: Dynamic modulation of ion channel expression, localization, and/or function drives plasticity in intrinsic neuronal excitability. Voltage-gated Kv2.1 potassium channels are constitutively maintained in a highly phosphorylated state in neurons. Increased neuronal activity triggers rapid calcineurin-dependent dephosphorylation, loss of channel clustering, and hyperpolarizing shifts in voltage-dependent activation that homeostatically suppress neuronal excitability. These changes are reversible, such that rephosphorylation occurs after removal of excitatory stimuli. Here, we show that cyclin-dependent kinase 5 (CDK5), a Pro-directed Ser/Thr protein kinase, directly phosphorylates Kv2.1, and determines the constitutive level of Kv2.1 phosphorylation, the rapid increase in Kv2.1 phosphorylation upon acute blockade of neuronal activity, and the recovery of Kv2.1 phosphorylation after stimulus-induced dephosphorylation. We also demonstrate that although the phosphorylation state of Kv2.1 is also shaped by the activity of the PP1 protein phosphatase, the regulation of Kv2.1 phosphorylation by CDK5 is not mediated through the previously described regulation of PP1 activity by CDK5. Together, these studies support a novel role for CDK5 in regulating Kv2.1 channels through direct phosphorylation.
authors.affiliation: Department of Neurobiology, Physiology, and Behavior, University of California, Davis, California 95616.
authors.forename: Oscar
authors.initials: O
authors.lastname: Cerda
authors.affiliation: Department of Neurobiology, Physiology, and Behavior, University of California, Davis, California 95616; Physiology and Membrane Biology, University of California, Davis, California 95616. Electronic address: jtrimmer@ucdavis.edu.
authors.forename: James S
authors.initials: JS
authors.lastname: Trimmer
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051663:Kv1.2 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D051381:Rats
chemical_list: D051663:Kv1.2 Potassium Channel; D009419:Nerve Tissue Proteins; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495907:Cdk5 protein, rat; D019703:Calcineurin; D054645:Protein Phosphatase 1