A short isoform of STIM1 confers frequency-dependent synaptic enhancement

Abstract

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 splice variant, STIM1B, which shows exclusive neuronal expression and protein content surpassing conventional STIM1 in cerebellum and of significant abundance in other brain regions. STIM1B expression results in a truncated protein with slower kinetics of ER-plasma membrane (PM) cluster formation and I_CRAC, 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 of synaptic plasticity.

Keywords: CICR; ICRAC; Orai; SOCE; endocytosis; localization; presynaptic ER; short-term enhancement; vesicles.