Li, BoxingTadross, Michael RTsien, Richard W2017-09-192017-09-192016-02-19https://hdl.handle.net/10161/15558Voltage-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 (Ca(2+)), voltage-dependent conformational change (VΔC), or a combination of the two has thus far been equivocal. We fused CaV1.2 to a ligand-gated Ca(2+)-permeable channel, enabling independent control of localized Ca(2+) and VΔC signals. This revealed an unexpected dual requirement: Ca(2+) must first mobilize actin-bound Ca(2+)/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 Ca(2+) 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.AnimalsAutistic DisorderCalcium Channel BlockersCalcium Channels, L-TypeCalcium SignalingCalcium-Calmodulin-Dependent Protein Kinase Type 2Cells, CulturedCyclic AMP Response Element-Binding ProteinGene Expression RegulationHEK293 CellsHippocampusHumansLong QT SyndromeNeuronal PlasticityNeuronsNimodipineProtein ConformationRatsRats, Sprague-DawleyReceptors, N-Methyl-D-AspartateSynapsesSyndactylyJournal article1095-9203