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. [Display omitted] ► Several factors underlie CaV1 privilege in triggering CREB-mediated gene expression ► CaV1 channels use local Ca2+ to trigger CaMKII-dependent signaling to the nucleus ► CaV2 channels elevate [Ca2+]i microns away to activate CaMKII near CaV1 channels ► CaV2-mediated Ca2+ rises are preferentially buffered by ER and mitochondria Voltage-gated calcium channels differentially influence activity-dependent gene expression. In hippocampal neurons, Cav1 channels efficiently trigger transcriptional output by directing calcium flux to localized CaMKII, whereas Cav2 channels are less efficient due to calcium buffering by nearby ER and mitochondria.