**1. Introduction**

Cell signaling is the network of reactions and interaction of molecules that allow cells to react to a wide range of stimuli. In this response, many pathways are involved, so cells are able to adapt to changing conditions. One of the mechanisms to respond to external stimuli is mediated by receptors, that is, proteins located at the plasma membrane that communicate the extracellular and the intracellular medium. A significant strategy that cells acquired early in their evolution was the modification of the composition of the intracellular milieu, so the ionic

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

composition is different across the plasma membrane. This strategy is expensive in terms of the consumption of energy, since the ionic composition of the intracellular medium is modified by pumping out some ions from the cytosol. However, this is cost-efficient because it provided the possibility to proliferate and to gain cellular specialization. In this regard, free calcium (Ca2+) concentration in the cytosol of cells is much lower than that observed in the external medium, so there are mechanisms to remove the excess of free Ca2+ from the cytosol, such as extruding Ca2+ to the extracellular medium or to intracellular Ca2+ stores. This pumping is carried out by plasma membrane Ca2+ pumps and by endoplasmic reticulum Ca2+ pumps, respectively. Also, buffering of Ca2+ with Ca2+-binding proteins is another strategy to keep cytosolic free Ca2+ concentration ([Ca2+]i) within the low nanomolar range (~100 nM). The reason why the [Ca2+]i is tightly controlled is because this level is a second messenger in cell signaling, that is, transient variations of [Ca2+]i communicate a signal to be transmitted. For instance, during fertilization of mammalian oocytes, a series of short-term cytosolic increases of [Ca2+]i occurs in the oocyte for ~20 h after the fusion with sperm. These transient and short spikes are required to release the arrest of the cell cycle and to stimulate the transition from the fertilized oocyte to 1-cell embryo (zygote). The level of [Ca2+]i is also involved in many other cellular events, like the control of gene expression, vesicular trafficking, neurotransmitter release, cytoskeletal dynamics, and so on.

Cytosolic Ca2+ spikes and Ca2+ waves are generated by the opening of Ca2+-specific ion channels located at the plasma membrane and subcellular organelles. When they become activated, plasma membrane Ca2+ channels let the influx of extracellular Ca2+ so the [Ca2+]i rapidly increases, triggering the activation of Ca2+-sensitive effectors. As the main intracellular Ca2+ store, the endoplasmic reticulum (ER) also contains Ca2+ channels that become activated upon certain stimuli to let the transient release of Ca2+ to the cytosol. Then, elevated [Ca2+] i activates Ca2+ pumps to reduce the level of free Ca2+ in the cytosol, making possible the temporal increase of [Ca2+]i which is essential for its role as a messenger. The speed of the Ca2+ rise, as well as the Ca2+ removal, together with the time that this elevation lasts, define the temporal Ca2+ signaling, or Ca2+ signature, a critical point in the activation of subsequent events. Similarly, the specific distribution of Ca2+ channels and pumps define the spatial Ca2+ signature. The spatiotemporal control of the Ca2+ signaling is relevant for determining the regulation of different signaling pathways that finally lead to diverse actions. In summary, it is not only important to know how Ca2+ levels are altered upon specific stimuli, but also their specific duration, shape, and subcellular localization.

STIM1L (the longest isoform), and STIM1S (the shortest isoform). For STIM2 gene, also three transcriptional variants have been described coding for proteins STIM2, STIM2.1 (or STIM2

**Table 1.** Accession number for genes and reference sequences (RefSeq) of transcriptional variants and proteins.

**Gene Transcript(s) Protein Protein official name** ENSG00000167323 NM\_001277961.1 NP\_001264890.1 STIM1 isoform 1, or STIM1L

ENSG00000109689 NM\_001169117.1 NP\_001162588.1 STIM2 isoform 3

ENSG00000160991 NM\_001126340.2 NP\_001119812.1 ORAI2 isoform a

ENSG00000276045 NM\_032790.3 NP\_116179.2 ORAI1

ENSG00000175938 NM\_152288.2 NP\_689501.1 ORAI3

NM\_003156.3 NP\_003147.2 STIM1 isoform 2 (canonical) NM\_001277962.1 NP\_001264891.1 STIM1 isoform 3, or STIMS

Regulation of Calcium Signaling by STIM1 and ORAI1 http://dx.doi.org/10.5772/intechopen.78587 5

NM\_001169118.1 NP\_001162589.1 STIM2.1, STIM2β NM\_020860.3 NP\_065911.3 STIM2.2, STIM2α

NM\_001271818.1 NP\_001258747.1 ORAI2 isoform a NM\_001271819.1 NP\_001258748.1 ORAI2 isoform b NM\_032831.3 NP\_116220.1 ORAI2 isoform a

Also in humans, three different genes code for ORAI proteins: ORAI1, ORAI2, and ORAI3. ORAI1 gene yields a single product (ORAI1 protein, also known as calcium release-activated calcium channel protein 1), whereas ORAI2 gene produces two variants (isoforms 1 and 2), and ORAI3 gene generates a single transcriptional variant and a single protein isoform

STIM1 protein is a positive regulator of store-operated Ca2+ entry (SOCE) [1, 2], a Ca2+ influx pathway regulated by the filling status of intracellular Ca2+ stores, mainly the ER. Although there is a significant pool of STIM1 at the plasma membrane, most STIM1 is ER-resident. When located at the ER, STIM1 shows a single transmembrane domain (TM) with the N-terminus toward the intraluminal space of this organelle. The Ca2+-sensitive EF-hand domain, together with a sterile-α-motif (SAM), constitute an intraluminal Ca2+ sensor, with an apparent dissociation constant for Ca2+ of 250 μM [3]. When the intraluminal Ca2+ concentration drops below this Kd, the dissociation of Ca2+ from the EF-hand domain is transmitted to the SAM domain, and to the cytosolic domain of the protein leading to its activation [4]. The cytosolic domain shows a well-studied calcium release-activated calcium (CRAC) activation domain (CAD), with a series of short coiled-coil (CC) domains that bind to ORAI1 plasma membrane channels to activate Ca2+ influx [5]. STIM1 protein also shows a Ser/Pro rich domain, close to a short sequence of four amino acids that binds to the microtubule plus-end binding protein EB1 [6], and finally a terminal Lys-rich domain which is critical for the activation of non-ORAI1 Ca2+

STIM2 and STIM1 share >60% sequence identity, and STIM2 also senses intraluminal Ca2+ concentration although with different sensitivity, since the dissociation constant for Ca2+

beta), and STIM2.2 (or STIM2 alpha) (see **Table 1**).

(**Table 1**).

channels, such as TRPCs [7].

In this chapter, we summarize the current knowledge regarding the role of the STIM and ORAI proteins family. Because of their role as ER intraluminal Ca2+ sensors, STIM proteins have been recently involved in the modulation of several Ca2+-dependent signaling pathways. ORAI proteins are Ca2+ channels located at the plasma membrane that regulate the influx of Ca2+, in some cases under the control of STIM proteins. Thus, cooperation of both proteins is critical for Ca2+ influx, Ca2+ signaling, and cell physiology.
