SK2 channel regulation of neuronal excitability, synaptic transmission, and brain rhythmic activity in health and diseases.

Abstract Small conductance calcium-activated potassium channels (SKs) are solely activated by intracellular Ca2+ and their activation leads to potassium efflux, thereby repolarizing/hyperpolarizing membrane potential. Thus, these channels play a critical role in synaptic transmission, and consequently in information transmission along the neuronal circuits expressing them. SKs are widely but not homogeneously distributed in the central nervous system (CNS). Activation of SKs requires submicromolar cytoplasmic Ca2+ concentrations, which are reached following either Ca2+ release from intracellular Ca2+ stores or influx through Ca2+ permeable membrane channels. Both Ca2+ sensitivity and synaptic levels of SKs are regulated by protein kinases and phosphatases, and degradation pathways. SKs in turn control the activity of multiple Ca2+ channels. They are therefore critically involved in coordinating diverse Ca2+ signaling pathways and controlling Ca2+ signal amplitude and duration. This review highlights recent advances in our understanding of the regulation of SK2 channels and of their roles in normal brain functions, including synaptic plasticity, learning and memory, and rhythmic activities. It will also discuss how alterations in their expression and regulation might contribute to various brain disorders such as Angelman Syndrome, Alzheimer's disease and Parkinson's disease.