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Review
. 2016 Jan 13:6:325.
doi: 10.3389/fphar.2015.00325. eCollection 2015.

STIM and Orai1 Variants in Store-Operated Calcium Entry

Juan A Rosado  1 , Raquel Diez  1 , Tarik Smani  2 , Isaac Jardín  1
Affiliations
Review

STIM and Orai1 Variants in Store-Operated Calcium Entry

Juan A Rosado et al. Front Pharmacol. .

Abstract

Store-operated Ca(2+) entry (SOCE) is an ubiquitous mechanism for Ca(2+) entry in eukaryotic cells. This route for Ca(2+) influx is regulated by the filling state of the intracellular Ca(2+) stores communicated to the plasma membrane channels by the proteins of the Stromal Interaction Molecule (STIM) family, STIM1, and STIM2. Store-dependent, STIM1-modulated, channels include the Ca(2+) release-activated Ca(2+) channels, comprised of subunits of Orai proteins, as well as the store-operated Ca(2+) (SOC) channels, involving Orai1, and members of the canonical transient receptor potential family of proteins. Recent studies have revealed the expression of splice variants of STIM1, STIM2, and Orai1 in different cell types. While certain variants are ubiquitously expressed, others, such as STIM1L, show a more restricted expression. The splice variants for STIM and Orai1 proteins exhibit significant functional differences and reveal that alternative splicing enhance the functional diversity of STIM1, STIM2, and Orai1 genes to modulate the dynamics of Ca(2+) signals.

Keywords: STIM1; STIM2; calcium entry; orai1; splice variants.

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Figures

FIGURE 1
FIGURE 1
(A) Molecular structure of STIM1 and STIM1L. (A) The ER luminal N-terminal region includes a Ca2+-binding canonical EF-hand motif (cEF), a hidden EF-hand (hEF) motif, and a sterile α-motif (SAM). STIM1 has a single transmembrane domainTM. The cytosolic C-terminal region includes three coiled-coil (CC) regions (CC1, CC2, and CC3), which contain the SOAR (STIM–Orai activating region) or CAD (CRAC activation domain), the minimal sequence required for the activation of Orai1 channels. Downstream of CC3 there is a C-terminal inhibitory domain (CTID), which overlaps the CRAC modulatory domain. The C-terminal region also contains a Pro/Ser-rich domain (PS) and a Lys-rich domain (K) (Soboloff et al., 2012). STIM1L also includes 106 amino acids located a position 515–620 (Darbellay et al., 2011). (B) Cartoon depicting a possible model of STIM1 monomer in the coalescent state, where STIM1 solved crystal structures are shown. CC1 is divided in CC1α1, CC1α2, and CC1α3 (Fahrner et al., 2014).
FIGURE 2
FIGURE 2
Molecular structure of STIM2 variants. (A) The ER luminal N-terminal region includes a Ca2+-binding canonical EF-hand motif (cEF), a non-Ca2+ -binding hidden EF-hand hEF motif, and a sterile α-motif (SAM). The cytosolic C-terminal region includes the CC regions (CC1 and CC2), the SOAR region a Pro/His-rich (PH) and a Lys-rich domain (K). The STIM2.1 variant contains an eight-residue insert (VAASYLIQ) in its SOAR region (Miederer et al., 2015; Rana et al., 2015). (B) Cartoon depicting a possible model of STIM2.2 monomer in the coalescent state, where STIM1 solved crystal structures conserved within STIM2 are shown. CC1 is divided in CC1α1, CC1α2, and CC1α3 (Fahrner et al., 2014).
FIGURE 3
FIGURE 3
Molecular structure of Orai1α and Orai1β variants. (A) Orai1α and Orai1β architecture. R, arginin-rich region; P, proline-rich region; RK, arginine-lysine-rich region; TM, transmembrane domain; CC, coiled-coil domain (Yuan et al., 2009; Derler et al., 2012). Orai1β has an alternative translation initiation from methionine at position 64 or 71 (Fukushima et al., 2012). (B) Cartoon depicting Orai1α monomer crystal structure in the resting state.
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