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

Abstract

Summary: 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. : Dittmer et al. show that postsynaptic activation of voltage-gated L-type Ca2+ channels triggers Ca2+ release from stores, activating feedback inhibition of L channels by the STIM1 Ca2+ sensor. Activated STIM1 also promotes L-channel-dependent growth in ER content of dendritic spines and attenuates nuclear translocation of the NFAT transcription factor. Keywords: voltage-gated Ca2+ channel, L-type Ca2+ channel, endoplasmic reticulum, stromal interaction molecule 1, N-methyl-D-aspartate receptor, dendritic spine, glutamate, structural plasticity, nuclear factor of activated T cells, cytoplasmic Ca2+