Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression

Voltage-gated Ca(V)1.2 channels (L-type calcium channel alpha 1C subunits) are critical mediators of transcription-dependent neural plasticity. Whether these channels signal via the influx of calcium ion (Ca2+), voltage-dependent conformational change (VDC), or a combination of the two has thus far been equivocal. We fused Ca(V)1.2 to a ligand-gated Ca2+-permeable channel, enabling independent control of localized Ca2+ and VDC signals. This revealed an unexpected dual requirement: Ca2+ must first mobilize actin-bound Ca2+/ calmodulin-dependent protein kinase II, freeing it for subsequent VDC-mediated accumulation. Neither signal alone sufficed to activate transcription. Signal order was crucial: Efficiency peaked when Ca2+ preceded VDC by 10 to 20 seconds. CaV1.2 VDC synergistically augmented signaling by N-methyl-D-aspartate receptors. Furthermore, VDC mistuning correlated with autistic symptoms in Timothy syndrome. Thus, nonionic VDC signaling is vital to the function of Ca(V)1.2 in synaptic and neuropsychiatric processes.