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

Science  19 Feb 2016:
Vol. 351, Issue 6275, pp. 863-867
DOI: 10.1126/science.aad3647

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Calcium channels deliver a one-two punch

To help generate long-lasting neuronal plasticity, CaV1.2 (L-type) calcium channels link electrical activity to nuclear gene expression. However, exactly how this coupling works is not fully understood. Li et al. developed a strategy to control two voltage-dependent signals—Ca2+ influx and non-ionic conformational changes—separately. The combinatorial delivery of both signals was required to maximize transcription. Ca2+ influx first mobilized the kinase CaMKII from the cytosol. This allowed subsequent voltage-dependent conformational changes to localize the kinase at CaV1.2 signaling hot spots. Abnormality of nonionic conformational signaling is associated with neurological dysfunction in Timothy syndrome, a highly penetrant form of autism-spectrum disorder.

Science, this issue p. 863

Abstract

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.

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