STIM1 Ca²⁺ Sensor Control of L-type Ca²⁺-Channel-Dependent Dendritic Spine Structural Plasticity and Nuclear...

Potentiation of synaptic strength relies on postsynaptic Ca²⁺ signals, modification of dendritic spine structure, and changes in gene expression. One Ca²⁺ signaling pathway supporting these processes routes through L-type Ca²⁺ channels (LTCC), whose activity is subject to tuning by multiple mechanisms. Here, we show in hippocampal neurons that LTCC inhibition by the endoplasmic reticulum (ER) Ca²⁺ sensor, stromal interaction molecule 1 (STIM1), is engaged by the neurotransmitter glutamate, resulting in regulation of spine ER structure and nuclear signaling by the NFATc3 transcription factor. In this mechanism, depolarization by glutamate activates LTCC Ca²⁺ influx, releases Ca²⁺ from the ER, and consequently drives STIM1 aggregation and an inhibitory interaction with LTCCs that increases spine ER content but decreases NFATc3 nuclear translocation. These findings of negative feedback control of LTCC signaling by STIM1 reveal interplay between Ca²⁺ influx and release from stores that controls both postsynaptic structural plasticity and downstream nuclear signaling.