Ask about this productRelated genes to: ORAI1 Blocking Peptide
- Gene:
- ORAI1 NIH gene
- Name:
- ORAI calcium release-activated calcium modulator 1
- Previous symbol:
- TMEM142A
- Synonyms:
- FLJ14466, CRACM1
- Chromosome:
- 12q24.31
- Locus Type:
- gene with protein product
- Date approved:
- 2006-04-10
- Date modifiied:
- 2019-04-23
Related products to: ORAI1 Blocking Peptide
Related articles to: ORAI1 Blocking Peptide
- Depletion of calcium from ER stores leads to the activation of calcium channels on the plasma membrane known as store-operated calcium entry. The proteins STIM1 and STIM2 function as ER calcium sensors, and upon store depletion, they undergo a conformational change that allows them to bind to and gate Orai calcium channels on the plasma membrane. We have shown that both Orai1 and STIM1 are dynamically S-acylated after store depletion, which is required for SOCE. These results suggest the requirement of a calcium-activated protein S-acyltransferase (PAT) such as DHHC21. Here, we show that DHHC21 is essential for SOCE in vitro and in vivo. Using the depilated mouse model that expresses DHHC21 but cannot be activated by calcium, we show that DHHC21 activation is a major mediator of STIM1 S-acylation and subsequent calcium entry. Plasma membrane-localized DHHC21 is dynamically recruited into Orai1/STIM1 puncta upon store depletion, where it physically binds to STIM1. Finally, we show that depilated mice phenocopy many aspects of autoimmune lymphoproliferative syndrome (ALPS), including defective Fas-mediated calcium release, T cell death, neutropenia, and increased serum vitamin B12 levels. Targeting DHHC21 may be therapeutically beneficial for ALPS and diseases associated with deregulated activation of STIM1, such as tubular aggregate myopathy and Stormorken syndrome. - Source: PubMed
Publication date: 2026/08/17
Kodakandla GouthamFan YingZhu Michael XWest Savannah JAkimzhanov AskarBoehning Darren - Cold-induced thermogenesis in brown adipose tissue is essential for maintaining energy homeostasis, yet the Ca-dependent mechanisms underlying this process remain incompletely understood. Here, we identify Orai1, a component of the store-operated Ca entry pathway, as a regulator of thermogenic activation in brown adipose tissue. Using a brown adipocyte-specific Orai1 knockout mouse model, we demonstrate that cold exposure is associated with Orai1-dependent Ca influx through a non-canonical mechanism. Orai1 deficiency impairs cAMP-protein kinase A signalling, reduces the expression of lipolytic enzymes and thermogenic genes, and diminishes mitochondrial Ca uptake and uncoupling. These defects culminate in cold intolerance, lipid accumulation and decreased energy expenditure. Mechanistically, Orai1 facilitates Ca-dependent activation of adenylyl cyclase 3, linking membrane Ca entry to cAMP production, and promotes mitochondrial remodelling and oxidative metabolism. These findings support a key role for Orai1 in coordinating Ca entry to lipolytic and mitochondrial pathways in brown adipocytes and highlight Orai1 as a potential therapeutic target in metabolic diseases characterized by impaired energy metabolism. - Source: PubMed
Publication date: 2026/08/13
Kim SujiNguyen Phan AnhPark Kyu-SangCha Seung-KuyNamkung Jun - Acute lung injury arising from acute pancreatitis or sepsis remains a major clinical challenge and lacks specific therapeutic strategies. Neutrophil activation and infiltration, tightly governed by intracellular Ca signaling via ORAI1-based Ca release-activated Ca (CRAC) channels, play central roles in the pathogenesis of acute lung injury. Here, we engineered a neutrophil-targeted lipid nanoparticle (neutLNP) encapsulating the selective CRAC channel inhibitor CM4620 (Anti-Ly6G@CM4620-LNP) for intranasal delivery. The neutLNP efficiently suppressed neutrophil chemotaxis and reactive oxygen species production, and significantly attenuated lung injury in both pancreatitis- and sepsis-associated lung injury models. Compared with intranasally administered free CM4620, neutLNP produced greater reductions in selected histological and inflammatory endpoints. Pulmonary imaging and flow cytometry demonstrated distribution within the inflamed lung parenchyma and preferential association with pulmonary neutrophils, whereas pharmacokinetic analysis showed markedly lower plasma CM4620 exposure after intranasal than after intraperitoneal administration. Mechanistically, integrated transcriptomic and single-cell proteomic profiling of pulmonary neutrophils from neutrophil-specific Orai1-deficient mice identified CD166 as a downstream mediator of ORAI1 signaling. Further analyses showed that ORAI1 signaling transcriptionally promotes CD166 expression, at least in part through NFATc2. Together, these findings support intranasal neutLNP delivery as a locally directed strategy that enhances lung protection relative to intranasal free CM4620 while limiting systemic exposure compared with intraperitoneal delivery, and establish CD166 as a functionally important downstream mediator of ORAI1-dependent neutrophil adhesion in acute inflammatory lung injury. - Source: PubMed
Publication date: 2026/08/12
Yang ZihanMeng QingyeZhu LiuQiu BintaoChen YonghaoLu WanyiZhang XiuliPeng KaixinWong Catherine C LWu DongWen Li - The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is a fundamental intracellular axis that integrates extracellular stimuli to orchestrate essential cellular processes. The activation of Akt1 represents a key determinant of aggressiveness in estrogen receptor positive (ER+) breast cancer, a process closely associated to Ca-signaling remodeling mediated by Orai1 and Orai3. In ER+ breast cancer cells, Orai3 plays a predominant role in store-operated Ca entry (SOCE), while Orai1 indirectly regulates SOCE and contributes to store-independent Ca influx pathways. Here we investigated the regulation of Akt1 activation by Orai3 and Orai1 and characterized the underlying intracellular mechanisms in ER+ breast cancer cells. Our findings reveal distinct, opposing roles for Orai1 and Orai3. Orai3 overexpression in wild-type cells, as well as 2-APB-mediated stimulation of Orai1-knockout (O1KO) MCF-7 cells, enhanced Akt1 phosphorylation, whereas Orai3 knockdown attenuated this effect. This 2-APB-induced activation was impaired by calmodulin-dependent protein kinase kinase (CaMKK) inhibition in a concentration-dependent manner. Conversely, Orai1 deficiency (O1KO) or shRNA-mediated knockdown resulted in enhanced Akt1 phosphorylation, while Orai1 overexpression attenuated it. Expression of the pore-dead Orai1E106Q mutant in O1KO cells failed to affect Akt phosphorylation, indicating that Ca influx is essential for this modulation. Mechanistically, Orai1 knockout or knockdown attenuated the expression of the adenylyl cyclase 8 (AC8), while Orai1 expression enhanced AC8 levels through a Ca-influx-dependent mechanism. Finally, silencing AC8 impaired Orai1-mediated inhibition of Akt phosphorylation. Overall, these findings demonstrate an unprecedented functional antagonism between Orai1 and Orai3 in ER+ breast cancer cells, where distinct signaling pathways mediate their opposing effects on Akt1 phosphorylation. - Source: PubMed
Publication date: 2026/08/11
Macías-Díaz AlvaroLopez Jose JFuentes-Mateos ManuelSmani TarikRosado Juan A - TAK-243, an inhibitor of the ubiquitin-activating enzyme UBA1, impairs the ubiquitination of proteins. We investigated its effects on the intracellular Ca dynamics of human prostate cancer cells DU-145. Live-cell Ca imaging with Fura2 showed that DU-145 cells exhibited spontaneous Ca transients that were largely independent of the activity of the Na/Ca exchanger but were abolished by extracellular Ca removal, La, Gd, BTP2 (Orai channel blocker), and thapsigargin (which depletes endoplasmic reticulum -ER- Ca stores). They were also sensitive to U73122 (a phospholipase C inhibitor) and dantrolene (a ryanodine receptor blocker), suggesting the contribution of both store-operated Ca channels and intracellular Ca release pathways in the generation and maintenance of these Ca spikes. At 0.2 μM, TAK-243 augmented the cytosolic concentration of Ca ([Ca]i), boosted the Ca spiking activity, whereas at 10 μM it caused a constitutive Ca entry through BTP2-sensitive Ca channels, which further augmented [Ca]i but reduced the number of spontaneously active cells. Experiments conducted with the genetically encoded Ca dye CEPIA1er showed that TAK-243 did not empty the ER Ca stores. Moreover, Förster resonance energy transfer (FRET) experiments on HEK-293 cells transfected with Orai1-CFP and STIM1-YFP indicated that it caused the relocalization of STIM1 and its coupling with Orai1. TAK-243 also increased the membrane potential and the Ca buffering capacities of mitochondria. Taken together, treating DU-145 cells with TAK-243 to prevent the ubiquitination of proteins activates the entry of Ca through store-operated Ca channels independently of the ER Ca stores and alters mitochondrial functions. - Source: PubMed
Publication date: 2026/08/03
Perrier MarieBenson J CoryFauvarque Marie-OdileTrebak MohamedBouron Alexandre