Short Novel STIM1B Uncovers a Mechanism of Synaptic Enhancement

Store-operated Ca2+-entry (SOCE) regulates basal and receptor-triggered Ca2+ signaling with STIM proteins sensing the endoplasmic reticulum (ER) Ca2+ content and triggering Ca2+ entry by gating Orai channels. Although crucial for immune cells, STIM1’s role in neuronal Ca2+ homeostasis is controversial. Here, we characterize a novel splice variant, STIM1B, with exclusive neuronal expression, protein content surpassing conventional STIM1 in cerebellum and significant abundance in hippocampus. STIM1B results in a truncated protein with slower kinetics of ER-PM cluster formation and ICRAC as well as reduced inactivation. In primary wild-type neurons, Stim1B is targeted by its spliced-in domain B to presynaptic sites where it converts classic synaptic depression into Ca2+- and Orai-dependent short-term synaptic enhancement (STE) at high frequency stimulation (HFS). In conjunction with altered STIM1 splicing in human Alzheimer disease, our findings highlight STIM1 splicing as an important regulator of neuronal calcium homeostasis and synaptic plasticity.