Molecular basis of interactions between CaMKII and α-actinin-2 that underlie dendritic spine enlargement

Abstract

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is essential for long-term potentiation (LTP) of excitatory synapses that is linked to learning and memory. In this study, we focused on understanding how interactions between CaMKIIα and the actin crosslinking protein α-actinin-2 underlie long-lasting changes in dendritic spine architecture. We found that association of the two proteins was unexpectedly elevated following stimulation of NMDA receptors to trigger structural LTP in primary hippocampal neurons. Furthermore, disruption of interactions between the two proteins prevented the accumulation of enlarged mushroom-type dendritic spines following NMDA receptor activation. α-actinin-2 binds to the regulatory segment of CaMKII. Calorimetry experiments, and a crystal structure of α-actinin-2 EF hands 3 and 4 in complex with the CaMKII regulatory segment, indicate that the regulatory segment of autoinhibited CaMKII is not fully accessible to α-actinin-2. Pull-down experiments show that occupation of the CaMKII substrate binding groove by GluN2B markedly increases α-actinin-2 access to the CaMKII regulatory segment. Overall, our study provides new mechanistic insight into the molecular basis of structural LTP and reveals an added layer of sophistication to the function of CaMKII.

Disruption of autism-associatedPcdh9gene leads to transcriptional alterations, synapses overgrowth and aberrant excitatory transmission in the CA1

“…Notably, Shank2 deficiency leads to a reduction in PSD thickness in the CA1 (46). Camk2a promotes activity-dependent spine enlargement by recruiting the actin cytoskeleton (47), and Dapk1 also functions in structural synaptic plasticity by regulating Camk2a binding to the NMDA receptor (NMDAR) subunit GluN2B (38). The PSD component Csmd2 promotes the development and maintenance of dendrites and synapses (37).…”