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

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/CaMKIIα complexes can be specifically co-immunoprecipitated from mouse forebrain lysates, and that purified activated (Thr286 autophosphorylated) CaMKIIα 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.