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CELL BIOLOGY OF THE NEURON Polarity ... - Tavernarakis Lab

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Cell Biology of the Neuron: <strong>Polarity</strong>, Plasticity and Regeneration, Crete 2011<br />

Cyclin-Dependent Kinase 5 Regulates Calcium Influx<br />

through N-type Calcium Channels<br />

Susan Su, Jennifer Pan, Benjamin Samuels, Khaing Win, Susan Zhang, David<br />

Yue, Li-Huei Tsai<br />

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase<br />

expressed in postmitotic neurons of the central nervous system and requires p35,<br />

its binding partner, for activity. Besides its well-known role in establishing the<br />

cytoarchitecture of the developing brain and its implication in a number of<br />

neurodegenerative diseases such as Alzheimer’s disease, amyotrophic lateral<br />

sclerosis (ALS), Neiman Pick’s Type C disease, and ischemic brain injury, recent<br />

evidence suggest that Cdk5 plays a key role in modulating synaptic functions. A<br />

growing list of characterized synaptic substrates include amphiphysin, dynamin,<br />

ephexin1, Munc-18, synapsin, and PSD-95, proteins that are involved in various<br />

functions such as vesicle trafficking, synapse formation and function or synaptic<br />

transmission. We previously showed that Cdk5 regulates synaptogenesis through<br />

phosphorylation of the presynaptic scaffolding molecule CASK. Upon<br />

phosphorylation by Cdk5, CASK dissociates from liprin-α, localizes to the<br />

synaptic compartment and associates with several presynaptic scaffolding<br />

proteins such as Mint1, Veli, and the α1B pore-forming subunit of the N-type<br />

voltage-gated calcium channels (CaV2.2), where it promotes calcium influx<br />

through CaV2.2 at presynaptic terminals. We now demonstrate that Cdk5<br />

interacts with and phosphorylates CaV2.2. Furthermore, from whole-cell patch<br />

clamp recordings in heterologous cells we observe that Cdk5/p35 causes a twofold<br />

increase in calcium influx through CaV2.2. Our results can provide novel<br />

insights into how Cdk5 modulates CaV2.2 to regulate synaptic function.<br />

Understanding Cdk5 signaling could lead to the development of new therapeutics<br />

targeting Cdk5 or CaV2.2 for neuropathic pain or neurodegenerative conditions.<br />

Presented by: Su, Susan<br />

191<br />

Poster No 109<br />

Red Session

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