STIM Proteins As Regulators of Neuronal Store-Operated Calcium Influx

Abstract

The store-operated calcium channels (SOC) were initially described in nonexcitable cells, such as T cells in the immune system [1]. In neurons, the presence of SOC has been controversial [2]. The main argument against neuronal SOC (nSOC) is that neurons possess many other calcium-permeable channels with high conductance, such as NMDA receptors and voltage-gated calcium channels. The existence, functional relevance and molecular identity of nSOC are still under investigation. However, recent molecular analysis of nSOC provided support to its existence and importance for neuronal function.SOC is mediated by two main components: endoplasmic reticulum (ER) Ca 2+ sensors STIM1 or STIM2 proteins [3] and plasma membrane (PM) Ca 2+ channels from Orai and TRPC protein families [1]. SOC in nonexcitable cells is activated by ER Ca 2+ depletion in response to activation of inositol (1,4,5)-trisphosphate receptors and Ca 2+ release from the ER. ER Ca 2+ concentration is sensed by helix-loop-helix structural domain (EF hand domain) in the luminal portion of STIM1. Following Ca 2+ depletion from the ER, STIM1 forms oligomers and translocates to ER-PM junctions [1]. Once located to ER-PM junctions, STIM1 binds to Orai proteins and activate SOC Ca 2+ influx, leading to an increase in intracellular Ca 2+ concentration. This cytoplasmic Ca 2+ abundance is sequestered by SERCA pump to the ER, refilling the stores. The EF hand domain of STIM2 proteins has significantly lower affinity for Ca 2+ than STIM1, and it has been established that STIM2 proteins primarily control steady-state ER and cytosolic Ca 2+ homeostasis [4]. Both STIM1 and STIM2 proteins are expressed in hippocampal neurons [5], and both of these proteins have been implicated in control of nSOC. Klejman et al. observed that STIM1 is colocalized with Orai1 upon depletion of Ca 2+ stores in dendrites and soma [6]. More recent reports suggested that STIM1 and Orai1 are colocalized and may interact with synaptopodin, a protein that regulates synaptic plasticity in hippocampal dendritic spines [7]. Activation of STIM1 and nSOC was described in hippocampal neurons following activation of type I metabotropic glutamate receptors (mGluR) or muscarinic acetylcholine receptors (mAChR) [8]. Notably, nSOC-independent functions of STIM1 in hipocampal neurons were also reported. It was suggested that STIM1 directly controls level of phosphorylation and surface expression of the AMPAR [9]. The role of STIM1 in control of neuronal L-type Ca 2+ channel activity [10] and feedback regulation of Ca 2+ signals in presynaptic terminals was reported [11]. Using optically controlled construct OptoSTIM1, Kyung et al. demonstrated that expression and activation of this construct in mouse hippocampus is able to induce nSOC Ca 2+ influx and promote contextual memory formation [12]. Majewski et al. observed improvements of contextual learning in STIM1 overexpressing mice [13]. These authors further demonstrated that overexpression of STIM1 does not influence long-term potentiaton (LTP) induction in...

Cytosolic calcium: Judge, jury and executioner of neurodegeneration in Alzheimer's disease and beyond

“…Importantly, therapeutic potential has been demonstrated in human neurons derived from AD patients, in which not only Ca 2+ signaling is normalized, but so too are lysosome, autophagosome, and mitochondrial functions 33,70 . In a similar vein, studies in model cells have implicated related pathways important in ER Ca 2+ handling, such as STIM2 and SOCE, in driving upstream AD pathophysiology 8,110 …”

Alterations of the Endoplasmic Reticulum (ER) Calcium Signaling Molecular Components in Alzheimer’s Disease

“…A direct connection between Aβ-induced synaptic mushroom spine loss and the neuronal SOCE pathway was reported in two studies. Popugaeva et al reported that the application of exogenous Aβ42 oligomers to hippocampal cultures or injection of Aβ42 oligomers directly into the hippocampal region resulted in the reduction of mushroom spines and activity of synaptic CaMKII, which were rescued by STIM2 overexpression [224]. Accordingly, similar findings were reported in APPKI hippocampal neurons accumulating extracellular Aβ42.…”

“…The store-operated Ca 2+ entry (SOCE) is an essential route for Ca 2+ uptake to replenish intracellular Ca 2+ stores [224]. The stromal interaction molecules STIM1 and STIM2 have been identified as essential components of SOCE and major sensors of the Ca 2+ concentration located in the ER membrane (reviewed in [225]).…”

Increased RyR2 open probability induces neuronal hyperactivity and memory loss with or without Alzheimer's disease–causing gene mutations

“…However, SOCE is downregulated in AD mouse models. 45,46,49,50 Hence, it is unclear how the potential activation of SOCE would contribute to the worsening of AD progression as a result of increased RyR2 Po. It is also important to note that the 5xFAD mouse strain is a supra-physiological and aggressive AD mouse model.…”

“…In addition, increased RyR2 Po may induce ER Ca 2+ store depletion, which may lead to activation of the store‐operated Ca 2+ entry (SOCE) pathway. However, SOCE is downregulated in AD mouse models 45,46,49,50 . Hence, it is unclear how the potential activation of SOCE would contribute to the worsening of AD progression as a result of increased RyR2 Po.…”