SOCE (store-operated Ca2+ entry) is a ubiquitous mechanism for Ca2+ influx in animal cells. In a recent issue of the Biochemical Journal, Brailoiu and colleagues reported that cocaine attenuates SOCE in rat brain microvascular endothelial cells, via a mechanism that requires the expression and activation of the sigma-1 receptor, a chaperone located in the endoplasmic reticulum–mitochondrion interface that modulates intracellular Ca2+ homoeostasis and cell survival. This study envisages a pathway through which cocaine modulates endothelial function via regulation of SOCE. The regulation of SOCE by sigma-1 receptors provides a novel and important pathway in Ca2+ signalling.
A number of physiological agonists induce spatiotemporal Ca2+ signals that finely modulate a plethora of cellular functions. Among the Ca2+-transport mechanisms involved in agonist-evoked Ca2+ mobilization, SOCE (store-operated Ca2+ entry) appears to have a special relevance. SOCE (also known as capacitative Ca2+ entry for its analogy to the function of a capacitor in an electrical circuit ) is a process whereby the discharge of Ca2+ stores within a cell secondarily activates Ca2+ influx across plasma membrane channels. The activation of SOCE has been widely demonstrated in both electrically excitable and non-excitable cells, where this event has been found to be important not only for maintaining the Ca2+ signals, via the replenishment of the intracellular Ca2+ stores following their discharge upon cell stimulation with agonists or supporting Ca2+ oscillations , but also for full activation of cellular functions, including migration, proliferation, platelet aggregation and muscle contraction [3,4].
Since the identification of SOCE by Putney, Jr, in 1986 , both the nature of the store-operated channels and the mechanism underlying channel gating by distantly located Ca2+ stores have been investigated extensively. A milestone in the investigation of SOCE was the identification in 2005 of STIM1 (stromal interaction molecule 1) as the Ca2+ sensor of the intracellular Ca2+ stores [5,6]. This observation was crucial for the identification of the store-operated channels and the characterization of channel gating. Current evidence indicates that Ca2+ store depletion leads to the activation of two types of STIM1-regulated channels, named CRAC (Ca2+ release-activated Ca2+) channels and the SOC (store-operated Ca2+) channels. The CRAC channels, the best characterized, exhibit a high specificity for Ca2+ and are composed of Orai1, Orai2 or Orai3 , whereas SOC channels are less specific for Ca2+ and consists of still uncharacterized heteromultimeric complexes of Orai1 and TRPC (transient receptor potential canonical) subunits [8–10]. Given the biological relevance of SOCE, the analysis of the mechanisms regulating this process has attracted the attention of the scientific community.
As mentioned above, SOCE has been reported in a large number of mammalian cells, including those forming the vascular endothelium. Endothelial cells are highly heterogeneous, and their phenotype varies between different organs and different segments of the vascular bed. In pulmonary arterial endothelial cells, SOCE has been reported to promote shape change, interendothelial gap formation and rearrangement of the actin cytoskeleton , as well as increase cell permeability .
Sigma-1 receptors are chaperone proteins that consist of 223 amino acids with two potential transmembrane domains. This receptor associates with GRP78 (glucose-related protein 78)/BiP (immunoglobulin heavy-chain-binding protein), an ER (endoplasmic reticulum) chaperone located at the MAM (mitochondria-associated ER membrane) domain . Given its ER location, with the ligand-binding site in the luminal surface of the ER membrane, the sigma-1 receptors ligands should exhibit hydrophobic or amphipathic properties , and includes opioids (e.g. pentazocine), steroids (e.g. pregnenolone sulfate), antipsychotic drugs (e.g. haloperidol) and cocaine . Sigma-1 receptors are ubiquitously expressed in mammalian tissues, including cells of the central nervous system such as neurons, astrocytes and oligodendrocytes , as well as in endothelial cells, where sigma-1 receptor ligands have been reported to impair Ca2+ entry via TRPC5 or TRPM3 (transient receptor potential melastatin 3) independently of the sigma-1 receptor .
Sigma-1 receptors modulate intracellular Ca2+ homoeostasis in different ways. The initial studies reported that, upon activation with pharmacological agonists, sigma-1 receptors attenuate the increase in the cytosolic free Ca2+ concentration evoked by ischaemia in cultured cortical neurons from embryonic rats , playing a relevant role in neuroprotection. Later on, it was reported that, upon ER Ca2+ store depletion or via ligand stimulation, sigma-1 receptors dissociate from GRP78/BiP, redistribute from the MAM to the entire ER network, and lead to a prolonged Ca2+ signalling into mitochondria via the Ins(1,4,5)P3 receptor in order to promote cell survival . Furthermore, sigma-1 receptors have been reported to play a role in the regulation of Ca2+ entry via L-type Ca2+ channels in rat retinal ganglion primary and cultured cells .
In this issue of the Biochemical Journal, the study by Brailoiu et al.  provides evidence for a protective role of sigma-1 receptors in brain microvascular endothelial cells through the regulation of SOCE. Sigma-1 receptors bind cocaine, which modulates endothelial function and increases blood–brain barrier permeability through the induction of PDGF (platelet-derived growth factor) . In this regard, Brailoiu et al.  report, in rat brain microvascular endothelial cells, that cocaine attenuates SOCE induced by thapsigargin (an inhibitor of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase that accumulates Ca2+ into the intracellular compartments). Despite cocaine being found to induce membrane depolarization by modifying the Na+/K+ permeability ratio in synaptosomes, which might lead to a reduction in the driving force for Ca2+ entry, the authors have reported that cocaine did not alter the membrane potential in endothelial cells at least for the time of the experiment. As reported, neither the ability of the cells to accumulate Ca2+ into intracellular stores nor the Ca2+ leakage rate from these stores are modified by cocaine, since Ca2+ efflux evoked by thapsigargin was not altered by the drug. Interestingly, the authors conclude that the effect of cocaine was mediated by the sigma-1 receptor. This statement is based on the impairment of cocaine-induced effects observed by silencing sigma-1 receptor expression or treatment with sigma-1 receptor inhibitors.
The inhibitory role of sigma-1 receptors on SOCE is consistent with the hypothesis that these receptors are involved in the promotion of cell survival through the modulation of intracellular Ca2+ homoeostasis , and might protect endothelial cells from the damage induced by cocaine and other sigma-1 receptor ligands.
There are a number of questions raised by the study of Brailoiu et al. . (i) What is the mechanism underlying the attenuation of SOCE by sigma-1 receptor activation? As mentioned by the authors, the activation of sigma-1 receptors might interfere with the activation of STIM1 or its interaction with the Orai1 and even the TRPC channels in the plasma membrane. Since the slope of the initial increase in cytosolic Ca2+ concentration upon readdition of Ca2+ in cells treated in the absence and presence of cocaine is similar, the regulatory mechanism is more likely to be a slow sigma-1 receptor-dependent inactivation of SOCE rather than a mechanism that affects the initial stage of SOCE activation. (ii) What is the functional relevance of sigma-1 receptors in the context of SOCE? (iii) Since sigma-1 receptors are involved in cell survival and modulate SOCE, which has been reported to be remodelled in certain cancer cell types, is their expression altered in cancer cells? (iv) If so, are sigma-1 receptor ligands suitable for anti-cancer therapy?
SOCE is a fascinating event in cellular biology and addressing the above-mentioned questions will shed new light not only on the regulatory mechanisms of SOCE, but also on the cellular effects of sigma-1 receptors.
Supported by the Ministerio de Economía y Competitividad (MINECO) [grant number BFU2013-45564-C2-1-P] and Junta de Extremadura of the Federación Española de Enfermedades Raras (FEDER) [grant number GR15029].
immunoglobulin heavy-chain-binding protein
Ca2+ release-activated Ca2+
glucose-related protein 78
mitochondria-associated ER membrane
store-operated Ca2+ entry
stromal interaction molecule 1
transient receptor potential canonical