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

See allHide authors and affiliations

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

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

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


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.

View Full Text