A short isoform of STIM1 confers frequency-dependent synaptic enhancement.

Store-operated Ca ²⁺ -entry (SOCE) regulates basal and receptor-triggered Ca ²⁺ signaling with STIM proteins sensing the endoplasmic reticulum (ER) Ca ²⁺ content and triggering Ca ²⁺ entry by gating Orai channels. Although crucial for immune cells, STIM1's role in neuronal Ca ²⁺ 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 Ca ²⁺ - 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.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)