Neuronal STIMulation at Rest

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Science Signaling  22 Jul 2014:
Vol. 7, Issue 335, pp. pe18
DOI: 10.1126/scisignal.2005556


Almost a decade has passed since first STIM, and later Orai, proteins were identified as the molecular constituents of store-operated calcium entry (SOCE). Their roles in immune function have been intensely investigated, but the roles of STIM and Orai in neuronal cells have been much less clear. Lalonde et al. show that when neurons are hyperpolarized or “at rest,” constitutive endoplasmic reticulum (ER) Ca2+ release leads to SOCE-mediated activation of neuronal transcription factors. Precisely why ER Ca2+ release is constitutive in neurons remains an important question. Irrespective of the answer, this observation provides an intriguing new perspective on why a relatively low-abundance, small-conductance channel such as Orai1 would be important in neurons, which contain a relative abundance of voltage-operated Ca2+ channels.

Cellular Ca2+ homeostasis is a complex energy-consuming process that involves multiple players and subcellular compartments. The calcium concentration ([Ca2+]) in the extracellular milieu is typically ~2 mM; at rest, cytosolic [Ca2+] is ~100 nM, and in the ER, [Ca2+] is close to 500 μM. Because of the existence of poorly defined “leak” channels, maintaining high [Ca2+] in the ER requires the constant activity of sarcoplamic and ER Ca2+-ATPase (SERCA) pumps. In most cells, this arrangement produces a stable ER [Ca2+], unless SERCA function is blocked. However, papers by Lalonde et al. (1) and Hartmann et al. (2) reveal that in neurons, ER [Ca2+] cannot be maintained unless there is constant Ca2+ influx across the plasma membrane (Fig. 1).

Fig. 1 Control of ER Ca2+ content in neurons.

The proteins and pathways pertinent to Ca2+ homeostasis in neurons are shown, with relative localized Ca2+ concentration indicated by yellow shading. The plasma membrane Ca2+-ATPase (PMCA) is responsible for the extrusion of Ca2+ from the cell. The neuron can be considered in four parts. (i) The neuron has hyperpolarized, blocking VGCC activity and causing ER Ca2+ depletion. (ii) ER Ca2+ depletion activates STIM and engages Orai, enabling SERCA activity and refilling the ER Ca2+ content. (iii) The resting neuron with some amount of ER Ca2+ depletion becomes depolarized, but the activated STIM inhibits VGCC activation. (iv) The ER Ca2+ content of the activated neuron has recovered, causing VGCC activation due to STIM disengagement, and normal ER Ca2+ content.


Voltage-gated calcium channels (VGCCs) are the most abundant Ca2+ channels in neurons, and store-operated calcium entry (SOCE) is a universal process that occurs in all cells, including neurons. SOCE is the process whereby ER Ca2+ depletion leads to Ca2+ influx across the plasma membrane. In most cells, ER Ca2+ depletion can be attributed to the activation of either inositol-1,4,5-trisphosphate or ryanodine receptor channels (InsP3Rs or RyRs, respectively) on the ER membrane and the subsequent release of ER Ca2+ through these channels. In principle, any event leading to ER Ca2+ depletion should induce SOCE; in neurons, this event may simply be the absence of Ca2+ influx through VGCCs when the neuron is silent (that is, near the resting membrane potential). When VGCC activity is low, the inability of neurons to maintain ER Ca2+ content leads to the activation of STIM1 and STIM2, proteins that are present in the ER membrane, through dissociation of Ca2+ from their luminal calcium-binding domains called EF hands, thereby facilitating Orai-mediated Ca2+ entry (3). In both cultured cerebellar granule neurons (1) and acutely isolated Purkinje neurons (2), the STIM moiety serving as the primary mediator of SOCE is STIM1. However, other studies have reported that STIM2 was the primary STIM present in hippocampal (4) and cortical (5) neurons. Further, genetic ablation of STIM2 in mice reduced life expectancy, caused memory defects, and protected neurons from ischemia-reperfusion (4). Consequently, it is surprising that both cerebellar granule neurons and Purkinje neurons exhibited predominantly STIM1-mediated SOCE. Future investigations focused on STIM expression patterns in specific neuronal cell types may lead to a better understanding of differential ER Ca2+ handling in neuronal subtypes and the context-specific roles of the different STIM moieties.

Given that Ca2+ entry through either SOCE or VGCC activity is required to maintain neuronal ER Ca2+ content, it is interesting to speculate about whether STIM1 inhibits VGCC (6, 7). Although the initial observations were made in vascular smooth muscle and T cells and focused on Cav1.2 (6, 7), STIM1-mediated suppression of VGCCs was implicated in the differentiation of neurons from mouse embryonic stem cells (8). Inhibition of VGCCs by STIM1 and STIM2 could have profound implications for excitability in neurons, because constitutive STIM activation in resting neurons would presumably lead to VGCC inhibition. In this scenario, STIMs would create resistance to activation that would need to be overcome in the transition from resting to excitation.

Lalonde et al. (1) link SOCE (distinct from depolarization-induced Ca2+ entry through VGCCs or NMDA-type glutamate receptors) as directly responsible for Sp4 activity. Sp4 is a neuron-specific transcription factor that is primarily controlled through ubiquitin-proteasome–mediated degradation. Sp4 regulates the expression of both tissue-specific genes and housekeeping genes, is degraded under depolarizing conditions, and profoundly affects memory and synaptic plasticity (9). Precisely why there would be a link between Ca2+ entering cells through Orai1, and not VGCCs, and Sp4 is not known, but may reflect local engagement of distinct effectors, leading to the initiation of alternate transcriptional programs.

The authors speculate that their findings may provide a new link between Ca2+ dysregulation and neuronal pathologies, such as schizophrenia, in which Sp4 abundance inversely correlates with disease symptoms (9, 10). However, the findings of the current studies (1, 2) also have implications for Alzheimer’s disease. Mutations in the ER membrane proteins presenilin 1 and 2 lead to familial Alzheimer’s disease, and these mutations have been shown to reduce ER Ca2+ leak (1113). Neurons are presumably sensitive to the loss of ER Ca2+ leak, because this would decrease engagement of SOCE and potentially alter downstream signaling, such as Sp4 activity. Future investigations of STIM function in neurons expressing presenilin mutants may improve our understanding of this relationship.

In another recent study, Hartmann et al. (2) used Purkinje neuron–specific STIM1 deletion to reveal that STIM1 is critical for metabotropic glutamergic synaptic transmission and cerebellar motor function. These defects were linked primarily to a STIM1 requirement for excitatory postsynaptic currents mediated by the transient receptor potential channel TRPC3. The ability of STIM1 to modulate TRPC function has been a highly controversial topic for many years. It is tempting to speculate that this controversy might stem from internal factors in Purkinje neurons (and some, but not all, other cell types) that support STIM-TRPC interactions. Defining these conditions would go a long way toward addressing this controversy.

Lalonde et al. have provided an intriguing new perspective on the roles of STIM and Orai in neurons. STIM and Orai provide a crucial source of Ca2+ when neurons are at rest, in order to maintain ER Ca2+ concentration (Fig. 1). In addition to this homeostatic function, STIM activation in neurons also regulates gene transcription through Sp4 (1) and probably other transcription factors. Given the defects in both memory (4) and motor control (2) observed in animals with neuron-specific STIM knockout, these STIM-dependent effects on Ca2+ handling can have profound effects in the brain. In considering the multifaceted roles of STIM1 in the control of Ca2+ signals (14), future investigations will be required to define the STIM targets responsible for these functions.


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