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

Abstract

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 co-exist 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. By 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 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.

Orai1-NFAT Signalling Pathway Triggered by T Cell Receptor Stimulation

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