CaV1 and CaV2 Channels Engage Distinct Modes of Ca2+ Signaling to Control CREB-Dependent Gene Expression

Activity-dependent gene expression triggered by Ca2+ entry into neurons is critical for learning and memory, but whether specific sources of Ca2+ act distinctly or merely supply Ca2+ to a common pool remains uncertain. Here, we report that both signaling modes coexist and pertain to CaV1 and CaV2 channels, respectively, coupling membrane depolarization to CREB phosphorylation and gene expression. CaV1 channels are advantaged in their voltage-dependent gating and use nanodomain Ca2+ to drive local CaMKII aggregation and trigger communication with the nucleus. In contrast, CaV2 channels must elevate [Ca2+]i microns away and promote CaMKII aggregation at CaV1 channels. Consequently, CaV2 channels are ∼10-fold less effective in signaling to the nucleus than are CaV1 channels for the same bulk [Ca2+]i increase. Furthermore, CaV2-mediated Ca2+ rises are preferentially curbed by uptake into the endoplasmic reticulum and mitochondria. This source-biased buffering limits the spatial spread of Ca2+, further attenuating CaV2-mediated gene expression.