Alternatively spliced STIM2.3 is an evolutionarily late store-operated Ca2+ entry regulator expressed in brain.

Ca2+ homeostasis is essential for cellular functions, with regulation by store-operated Ca2+ entry (SOCE) omnipresent. Due to a lower affinity for endoplasmic reticulum (ER)-luminal Ca2+, STIM2 regulates basal cytosolic Ca2+ but also increases interaction and activation of ORAI proteins at ER-plasma membrane junctions after stimulation, whereas STIM1 requires stronger store depletion. In brain, STIM2 is highly expressed in hippocampal neurons. Here, we describe a short STIM2 splice variant, STIM2.3 (also known as STIM2G), that is present only in Old World monkeys, apes and humans, with expression mostly in brain. In contrast to other variants and despite lack of the polybasic domain, expression of STIM2.3 increased SOCE. Structure-function analysis delineated the role of the C-terminal motifs of STIM2 for Ca2+ entry as well as for basal and induced activation of the NFAT transcription factor NFATc1. STIM2.3 displayed reduced interaction with AMPK and with activated AMPK. Neuronal expression of STIM2.3, in comparison to STIM2.2, increased the size of dendritic spine heads, suggesting a specific regulatory role in spine maintenance. Regulated splicing of STIM2.3 in brain might present a rapid mechanism to increase STIM2-mediated effects on gene expression, spine morphology or spontaneous excitability, potentially facilitating an evolutionarily recent expansion of brain complexity.