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bioRxiv · 10.1101/551648

Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction

Perfitt, T. L.·Wang, X.·Stephenson, J. R.·Nakagawa, T.·Colbran, R. J.
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Abstract

The molecular mechanisms that couple plasma membrane receptors/channels to specific intracellular responses, such as increased gene expression, are incompletely understood. The postsynaptic scaffolding protein Shank3 associates with Ca2+ permeable receptors or ion channels that can activate many downstream signaling proteins, including calcium/calmodulin-dependent protein kinase II (CaMKII). Here, we show that Shank3/CaMKII complexes can be specifically co-immunoprecipitated from mouse forebrain lysates, and that purified activated (Thr286 autophosphorylated) CaMKII binds directly to Shank3 between residues 829-1130. Mutation of three basic residues in Shank3 (R949RK951) to alanine disrupts CaMKII binding to Shank3 fragments in vitro, as well as CaMKII association with full-length Shank3 in heterologous cells. Our shRNA/rescue studies revealed that Shank3 binding to both CaMKII and L-type calcium channels (LTCCs) is required for increased phosphorylation of the nuclear CREB transcription factor induced by depolarization of cultured hippocampal neurons. Thus, this novel Shank3-CaMKII interaction is essential for the initiation of a specific long-range signal from plasma membrane LTCCs to the nucleus that is required for activity-dependent changes in neuronal gene expression during learning and memory.

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Perfitt, T. L., Wang, X., Stephenson, J. R., Nakagawa, T., Colbran, R. J.. 2019-02-16. Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction. https://doi.org/10.1101/551648

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