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Neuron DOI:10.1016/j.neuron.2012.06.023

Regulation of N-type voltage-gated calcium channels and presynaptic function by cyclin-dependent kinase 5.

Publication TypeJournal Article
Year of Publication2012
AuthorsSu, SC, Seo, J, Pan, JQ, Samuels, BAdam, Rudenko, A, Ericsson, M, Neve, RL, Yue, DT, Tsai, L-H
Date Published2012 Aug 23
KeywordsAmiodarone, Analysis of Variance, Animals, Biophysics, Biotinylation, Calcium Channels, N-Type, Cells, Cultured, Cerebral Cortex, Cyclin-Dependent Kinase 5, Electric Stimulation, Embryo, Mammalian, Excitatory Postsynaptic Potentials, Gene Expression Regulation, Green Fluorescent Proteins, Hippocampus, Humans, Immunoprecipitation, In Vitro Techniques, Ion Channel Gating, Male, Mice, Mice, Inbred C57BL, Microscopy, Electron, Transmission, Models, Molecular, Mutation, Nerve Tissue Proteins, Neurons, Patch-Clamp Techniques, Phosphorylation, Phosphotransferases, Presynaptic Terminals, Radioimmunoassay, Sequence Analysis, Protein

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.


Alternate JournalNeuron
PubMed ID22920258
PubMed Central IDPMC3428598
Grant ListR01 GM053049 / GM / NIGMS NIH HHS / United States
R01 MH065531 / MH / NIMH NIH HHS / United States
R01 NS051874 / NS / NINDS NIH HHS / United States
T32 MH074249 / MH / NIMH NIH HHS / United States