Nuclear BK channels regulate gene expression via the control of nuclear calcium signaling

Ion channels are essential for the regulation of neuronal functions. The significance of plasma membrane, mitochondrial, endoplasmic reticulum and lysosomal ion channels in the regulation of Ca²⁺ is well established. In contrast, surprisingly little is known about the function of ion channels on the nuclear envelope (NE). Here we demonstrate the presence of functional large-conductance, calcium-activated potassium channels (BK channels) on the NE of rodent hippocampal neurons. Functionally, blockade of nuclear BK channels (nBK channels) induces NE-derived Ca²⁺ release, nucleoplasmic Ca ²⁺ elevation and cyclic AMP response element binding protein (CREB)-dependent transcription. More importantly, blockade of nBK channels regulates nuclear Ca²⁺ -sensitive gene expression and promotes dendritic arborization in a nuclear Ca²⁺ -dependent manner. These results suggest that the nBK channel functions as a molecular link between neuronal activity and nuclear Ca²⁺ to convey signals from synapse to nucleus and is a new modulator, operating at the NE, of synaptic activity-dependent neuronal functions.