Since many cardiomyopathies involve Ca(+2) dysregulation, the role of SOCE in heart function has been investigated. SOCE (store-operated Ca(2+) entry) is a major mechanism for Ca(+2) influx and plays a key role in maintaining cellular calcium balance. SOCE is effected by an ER-plasma membrane-spanning channel named the Ca(2+) release-activated Ca(2+) channel (CRAC). In human, the primary and best characterized components of the CRAC are encoded by the genes STIM1 and ORAI1. Related genes include STIM2, ORAI2, and ORAI3.
For both the STIM and ORAI human gene families, member genes have been implicated in tubular aggregate myopathy (TAM; MIM:160565, MIM:615883). Mutations associated with TAM are thought to result in constitutive activity (as opposed to loss of function genotypes characterized in this model).
A UAS construct of Hsap\ORAI1 has been introduced into flies, but has not been characterized. Several UAS constructs of the human Hsap\STIM1 gene have been introduced into flies, including wild-type and genes carrying modifications of regulatory phosphorylation sites.
In Drosophila, there is a single gene in the STIM family, Stim, and a single gene in the ORAI family, Orai. See the FlyBase gene group report ‘Calcium release-activated calcium channel subunits’ (FBgg0000592). The lack of redundancy facilitates functional analysis in the fly model. A variety of genetic reagents, including RNAi and overexpression constructs, are available for both genes.
Animals homozygous for loss-of-function mutations of Dmel\Orai or Dmel\Stim typically die in the larval stage. To study effects of reduced function in the adult heart, RNAi-mediated knockdown specifically in the developing heart has been used. In animals with RNAi targeted to either Orai or Stim, phenotypes in the adult heart indicative of dilated cardiomyopathy are observed; myofibrils are highly disorganized and loosely spaced.
Dmel\Stim has also been studied in the context of human susceptibility to obesity; see ‘obesity, susceptibility to (postulated), STIM1-related’ (FBhh0001051). In that system, regulation of phosphorylation of Hsap\STIM1 has been investigated in flies in the context of signaling pathways regulated by exercise.
[updated Sep. 2020 by FlyBase; FBrf0222196]
Upon Ca(2+) depletion in the ER, the STIM1 protein translocates to ER-plasma membrane junctions and binds to ORAI1 subunits in the plasma membrane, forming and activating Ca(2+) release-activated Ca(2+) (CRAC) channels (Lacruz and Feske, 2015; pubmed:26469693).
STIM1 encodes a type 1 transmembrane protein that mediates Ca(2+) influx after depletion of intracellular Ca(2+) stores by gating of store-operated Ca(2+) influx channels (SOCs). [Gene Cards, STIM1; 2020.09.12]
ORAI1, ORAI2, and ORAI3 encode membrane calcium channel subunits; the channel is activated by the calcium sensor STIM1 when calcium stores are depleted. Orai proteins form the channel pore. [Gene Cards, ORAI1, ORAI2, ORAI3; 2020.09.12]
Store-operated Ca(2+) entry (SOCE) is a mechanism for Ca(2+) entry through plasma membrane Ca(2+)-permeable channels modulated by the intracellular Ca(2+) stores, primarily of the endoplasmic reticulum (ER). This highly selective channel is termed Ca(2+) release-activated Ca(2+) channel (CRAC). In human, CRAC consists of the STIM1-encoded ER-Ca(2+) sensor and Orai subunits that form the channel pore. (Lopez et al., 2016, pubmed:27130253; Shim et al., 2016, pubmed:25284754)
Many to one: 2 human genes to 1 Drosophila gene.
Many to one: 2 human genes to 1 Drosophila gene.
Many to one: 3 human gene to 1 Drosophila gene.
Many to one: 3 human gene to 1 Drosophila gene.
Many to one: 3 human gene to 1 Drosophila gene.
Moderate-scoring ortholog of human ORAI1, ORAI2, and ORAI3 (1 Drosophila to 3 human). Dmel\Orai shares 40-50% identity and 54-62% similarity with the human genes. The Drosophila gene encodes multiple isoforms, all longer than the human proteins; the fly proteins have 140-230 additional residues at the amino end.
Moderate- to high-scoring ortholog of human STIM1 and STIM2 (1 Drosophila to 2 human). Dmel\Stim shares 38-39% identity and 57-58% similarity with the human genes.
