Alternatively-spliced STIM2.3 is an evolutionary late Store-operated Calcium Entry regulator expressed in brain

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