STIM1 Ca 2+ Sensor Control of L-type Ca 2+ -Channel-Dependent Dendritic Spine Structural Plasticity and Nuclear Signaling

Potentiation of synaptic strength relies on postsynaptic Ca 2+ signals, modification of dendritic spine structure, and changes in gene expression. One Ca 2+ signaling pathway supporting these processes routes through L-type Ca 2+ 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) Ca 2+ 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 Ca 2+ influx, releases Ca 2+ 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 Ca 2+ influx and release from stores that controls both postsynaptic structural plasticity and downstream nuclear signaling.