REGULATION OF NEURONAL L-TYPE Ca2+ CHANNEL SIGNALING TO THE NUCLEUS THROUGH AUTISM-LINKED PROTEINS SHANK3 AND CAMKII

Abstract

Precise regulation of neuronal gene transcription is essential for normal brain function. For instance, neuronal depolarization leads to phosphorylation of the nuclear transcription factor CREB (pCREB), a critical transcription factor in learning and memory, and the expression of immediate early genes such as c-Fos. Such activity-dependent gene expression is disrupted in neurodevelopmental disorders, such as Autism Spectrum Disorder (ASD). These disorders often arise from mutations in synaptic proteins that interact with each other in large multi-protein complexes, such as CaMKII, Shank3, and L-type Ca2+ Channels (LTCCs). However, the molecular basis for formation of these complexes and the roles of specific protein-protein interactions in activity-dependent gene expression are poorly understood. We characterized a novel protein-protein interaction between CaMKII and Shank3, in addition to confirming interactions between each protein and LTCC CaV1.3. Our data show that each of the protein-protein interactions within this synaptic signaling complex is required for depolarization-induced phosphorylation of the CREB transcription factor in the nucleus. Moreover, the components of this complex are important for downstream expression of the c-Fos immediate early gene.