SK channels influence neuronal excitability, synaptic plasticity, and memory acquisition. SK channels are gated solely by intracellular Ca2+ ions and Ca2+ gating is endowed to SK channels by a constitutive interaction with the prototypic Ca2+ sensor, calmodulin (CaM). We have recently found that protein kinase CK2 and protein phosphatase 2a (PP2a) associate with SK2 channels in brain. CK2 and PP2a, respectively, phosphorylate and de-phosphorylate SK2-associated CaM on T80. The overall goal for our proposal is to determine the physiological significance of CK2 and PP2a mediated SK2 modulation in hippocampal CA1 neurons. We hypothesize that the N- and C-termini of the channel form a binding framework for CK2, and that PP2a is bound to the C-terminus of SK2. Positive charges in the N-terminus activate CK2, while spatially proximal negative charges in the C-terminal domain, induced by phosphorylation, reduce kinase activity. This mechanism allows CK2 and PP2a to regulate SK2's inhibitory effects on NMDA receptor activation in hippocampal CA1 neurons. Structure-function studies combined with biochemical protein dissection and lentiviral transgene expression provide a powerful methodology to rigorously test our hypotheses. ? ?
