Divergent interplay between STIM1 and STIM2 sets the efficacy of central synapses

Stromal interaction molecules (STIMs) are endoplasmic reticulum resident calcium (Ca²⁺ sensors that modulate Ca²⁺ homeostasis. Mammals express two isoforms, STIM1 and STIM2, but whether they serve redundant or distinct roles in neurotransmission remains poorly defined. Using Ca²⁺ imaging and electrophysiology in hippocampal neurons lacking STIM1, STIM2, or both, we examined presynaptic and postsynaptic functions of STIMs at excitatory and inhibitory synapses. Both isoforms redundantly activated store-operated Ca²⁺ entry and amplified presynaptic Ca²⁺ influx, sustaining neurotransmitter release by expanding the readily releasable pool of synaptic vesicles and accelerating vesicle replenishment. These presynaptic roles were synapse specific: STIM1 predominantly supported excitatory synapses, whereas STIM2 was critical for the inhibitory counterparts. Postsynaptically, STIM1 and STIM2 exerted opposing effects on glutamate and GABA receptor levels, such that simultaneous loss of both isoforms rescued postsynaptic function. Together, the findings show that STIM1 and STIM2 differentially tune synaptic efficacy according to synapse type and subcellular compartment.