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.
| Original language | English |
|---|---|
| Pages (from-to) | 675-687 |
| Number of pages | 13 |
| Journal | Neuron |
| Volume | 75 |
| Issue number | 4 |
| DOIs | |
| State | Published - 23 Aug 2012 |
Bibliographical note
Funding Information:We thank Dr. Diane Lipscombe for the rat Ca V 2.2 stable cell lines and Ca V 2.2 cDNA constructs and Dr. Kevin P. Campbell for the β3 cDNA construct. We are grateful for the assistance of Louise Trakimas at the Harvard Medical School Electron Microscopy facility. We acknowledge Dr. Haoya Liang for initial observations, Susan Zhang and Khaing Win for technical support, Drs. Karun Singh and Alison Mungenast for critical reading of the manuscript, Dr. Zhigang Xie, and members of the Tsai lab for discussions. S.C.S. was supported by NIH T32 MH074249 and a Norman B. Leventhal fellowship. A.R. is a recipient of the NARSAD Young Investigator Award. This work is supported by NIH R01 MH065531 to D.T.Y. and NIH R01 NS051874 to L.-H.T. L.-H.T. is an investigator of the Howard Hughes Medical Institute.