title: Regulation of N-type voltage-gated calcium channels and presynaptic function by cyclin-dependent kinase 5.
abstract: N-type voltage-gated calcium channels localize to presynaptic nerve terminals and mediate key events including synaptogenesis and neurotransmission. While several kinases have been implicated in the modulation of calcium channels, their impact on presynaptic functions remains unclear. Here we report that the N-type calcium channel is a substrate for cyclin-dependent kinase 5 (Cdk5). The pore-forming α(1) subunit of the N-type calcium channel is phosphorylated in the C-terminal domain, and phosphorylation results in enhanced calcium influx due to increased channel open probability. Phosphorylation of the N-type calcium channel by Cdk5 facilitates neurotransmitter release and alters presynaptic plasticity by increasing the number of docked vesicles at the synaptic cleft. These effects are mediated by an altered interaction between N-type calcium channels and RIM1, which tethers presynaptic calcium channels to the active zone. Collectively, our results highlight a molecular mechanism by which N-type calcium channels are regulated by Cdk5 to affect presynaptic function.
authors.affiliation: The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Su
authors.forename: Jinsoo
authors.initials: J
authors.lastname: Seo
authors.forename: Jen Q
authors.initials: JQ
authors.lastname: Pan
authors.forename: Benjamin Adam
authors.initials: BA
authors.lastname: Samuels
authors.forename: Andrii
authors.initials: A
authors.lastname: Rudenko
authors.forename: Maria
authors.initials: M
authors.lastname: Ericsson
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: David T
authors.initials: DT
authors.lastname: Yue
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
mesh_terms: D000638:Amiodarone; D000704:Analysis of Variance; D000818:Animals; D001703:Biophysics; D019921:Biotinylation; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D011863:Radioimmunoassay; D020539:Sequence Analysis, Protein
chemical_list: C500963:Cacna1b protein, mouse; D020864:Calcium Channels, N-Type; C492236:Cdk5r1 protein, mouse; D009419:Nerve Tissue Proteins; D049452:Green Fluorescent Proteins; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; D000638:Amiodarone