SUMMARY Activity-dependent CREB phosphorylation and gene expression are critical for long-term neuronal plasticity. Local signaling at CaV1 channels triggers these events but how information is relayed onward to the nucleus remains unclear. Here we report a novel mechanism that mediates long-distance communication within cells: a shuttle that transports Ca2+/calmodulin from the surface membrane to the nucleus. We show that the shuttle protein is γCaMKII, that its phosphorylation at Thr287 by βCaMKII protects the Ca2+/CaM signal, and that CaN triggers its nuclear translocation. Both βCaMKII and CaN act in close proximity to CaV1 channels, supporting their dominance, while γCaMKII operates as a carrier, not as a kinase. Upon arrival within the nucleus, Ca2+/CaM activates CaMKK and its substrate CaMKIV, the CREB kinase. This mechanism resolves longstanding puzzles about CaM/CaMK-dependent signaling to the nucleus. The significance of the mechanism is emphasized by dysregulation of CaV1, γCaMKII, βCaMKII and CaN in multiple neuropsychiatric disorders.

Voltage-gated CaV1.2 channels (L-type calcium channel α1C subunits) are critical mediators of transcription-dependent neural plasticity. Whether these channels signal via the influx of calcium ion (Ca2+), voltage-dependent conformational change (VΔC), or a combination of the two has thus far been equivocal. We fused CaV1.2 to a ligand-gated Ca2+-permeable channel, enabling independent control of localized Ca2+ and VΔC signals. This revealed an unexpected dual requirement: Ca2+ must first mobilize actin-bound Ca2+/calmodulin-dependent protein kinase II, freeing it for subsequent VΔC-mediated accumulation. Neither signal alone sufficed to activate transcription. Signal order was crucial: Efficiency peaked when Ca2+ preceded VΔC by 10 to 20 seconds. CaV1.2 VΔC synergistically augmented signaling by N-methyl-D-aspartate receptors. Furthermore, VΔC mistuning correlated with autistic symptoms in Timothy syndrome. Thus, nonionic VΔC signaling is vital to the function of CaV1.2 in synaptic and neuropsychiatric processes.

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 less 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 Ca2+ elevation, and cAMP 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 nBK channel functions as a molecular linker between neuronal activity and nuclear Ca2+ to convey the signals from synapse to nucleus and is a new modulator for synaptic activity-dependent neuronal functions at the NE level.

Ion channels are found in a variety of cancer cells and necessary for cell cycle and cell proliferation. The roles of K(+) channels in the process are, however, poorly understood. In the present study, we report that adenosine triphosphate (ATP)-sensitive potassium channel activity plays a critical role in the proliferation of glioma cells. The expression of K(ATP) channels in glioma tissues was greatly increased than that in normal tissues. Treatment of glioma cells with tolbutamide, K(ATP) channels inhibitor, suppressed the proliferation of glioma cells and blocked glioma cell cycle in G(0)/G(1) phase. Similarly, downregulation of K(ATP) channels by small interfering RNA (siRNA) inhibited glioma cell proliferation. On the other hand, K(ATP) channels agonist diazoxide and overexpression of K(ATP) channels promoted the proliferation of glioma cells. Moreover, inhibiting K(ATP) channels slowed the formation of tumor in nude mice generated by injection of glioma cells. Whereas activating K(ATP) channels promoted development of tumor in vivo. The effect of K(ATP) channels activity on glioma cells proliferation is mediated by extracellular signal-regulated kinase (ERK) activation. We found that activating K(ATP) channel triggered ERK activation and inhibiting K(ATP) channel depressed ERK activation. U-0126, the mitogen-activated protein kinase kinase (MAPK kinase) inhibitors blocked ERK activation and cell proliferation induced by diazoxide. Furthermore, constitutively activated MEK plasmids transfection reversed the inhibitory effects of tolbutamide on glioma proliferation, lending further support for a role of ERK in mediating this process. Our results suggest that K(ATP) channels control glioma cell proliferation via regulating ERK pathway. We concluded that K(ATP) channels are important in pathological cell proliferation and open a promising pathway for novel targeted therapies.