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

Abstract

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—Ca 2+ influx and non-ionic conformational changes—separately. The combinatorial delivery of both signals was required to maximize transcription. Ca 2+ 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