Coupling of Ca++ signals with pre-mRNA elements that are sufficient to mediate Ca++-regulated alternative splicing. Shown is a diagram of the pathway from membrane depolarization to the CaRRE and the UAGG motifs. In several neuronal or endocrine cells as indicated, membrane depolarization induces Ca++ signals through L-type Ca++ channels, likely activating CaMK IV, which targets pre-mRNA elements CaRRE1 and 2, probably also the UAGG motif, to control the inclusion of the exons, for example, STREX exon of Slo or exons 5 and 21 of NMDAR1. The changed exon compositions will later translate into proteins with different electrical properties (STREX, exon 5) or subcellular localizations (exon 21) to incorporate into the ion channels in cell membranes, to impact cellular electrical properties. In the pre-mRNA, the branch point (A), polypyrimidine tract (Yn) and 3′ AG (ag), and the exons (boxes) and introns (lines) are indicated. The CaRREs or the UAGG motif is shown as red bars. CaRRE1 was found in the upstream intron of the STREX exon and the NMDAR1 exon 5, and CaRRE1, 2 and UAGG motifs in the NMDAR1 exon 21. hnRNPA1 and the unknown factors are as red ovals. The “?” next to the hnRNP A1 pathway is to reflect the fact that this regulation requires CaM kinases but an effect by CaMK IV is not demonstrated yet.