STIM Proteins and Glutamate Receptors in Neurons: Role in Neuronal Physiology and Neurodegenerative Diseases

Abstract

Neuronal calcium (Ca2+) influx has long been ascribed mainly to voltage-gated Ca2+ channels and glutamate receptor channels. Recent research has shown that it is also complemented by stromal interaction molecule (STIM) protein-mediated store-operated Ca2+ entry (SOCE). SOCE is described as Ca2+ flow into cells in response to the depletion of endoplasmic reticulum Ca2+ stores. The present review summarizes recent studies that indicate a relationship between neuronal SOCE that is mediated by STIM1 and STIM2 proteins and glutamate receptors under both physiological and pathological conditions, such as neurodegenerative disorders. We present evidence that the dysregulation of neuronal SOCE and glutamate receptor activity are hallmarks of acute neurodegenerative diseases (e.g., traumatic brain injury and cerebral ischemia) and chronic neurodegenerative diseases (e.g., Alzheimer’s disease and Huntington’s disease). Emerging evidence indicates a role for STIM proteins and glutamate receptors in neuronal physiology and pathology, making them potential therapeutic targets.

STIM Protein-NMDA2 Receptor Interaction Decreases NMDA-Dependent Calcium Levels in Cortical Neurons

“…In conclusion, our results demonstrate that NMDAR, in addition to Orai, TRPC, VGCC, and AMPAR, comprise putative Ca 2+ sources for nSOCE [21,31]. Moreover, our findings presented here reveal a previously unidentified function of STIMs in neuronal signaling by interacting with NMDARs.…”

“…Ca 2+ influx into neuronal cells depends on NMDARs, AMPARs, VGCCs, as well as SOCE that trigger Orai/TRPs channels and STIM proteins [20,21,[34][35][36]. The role of NMDARs in nSOCE remains unclear.…”

“…STIM and NMDAR abnormalities have been implicated in the pathogenesis of neurodegenerative diseases [20,21]. However, the links between these proteins under normal and disease conditions remain unclear.…”

“…In fact, the role of STIM proteins in this process is debated given the complex regulation of Ca 2+ inflow through various receptors and Ca 2+ channels [17][18][19]. nSOCE was identified in cortical, hippocampal, cerebellar, dorsal root ganglion, and dorsal horn neurons (reviewed in [19][20][21]) and shown to regulate synaptic plasticity, neurotransmitter release, and gene expression [22][23][24][25][26]. The complex relationships among various Ca 2+ influx pathways in neurons have only been partly elucidated.…”

Excitotoxicity: Still Hammering the Ischemic Brain in 2020

“…4. Store-operated Ca 2+ entry provides Ca 2+ entry and replenishment of ER Ca 2+ stores in both non-excitable cells and excitable cells, and has been implicated in the pathogenesis of excitotoxicity and ischemic brain damage (Li et al, 2015;Serwach and Gruszczynska-Biegala, 2019). The system consists of Orai1-3, plasma membrane channels selective for Ca 2+ [blocked by Zn 2+ (Gore et al, 2004)] and gated by the ER Ca 2+ sensors, stomal interaction molecule isoforms, STIM1-2.…”