Ask about this productRelated genes to: STIM1 Blocking Peptide
- Gene:
- STIM1 NIH gene
- Name:
- stromal interaction molecule 1
- Previous symbol:
- -
- Synonyms:
- GOK, D11S4896E
- Chromosome:
- 11p15.4
- Locus Type:
- gene with protein product
- Date approved:
- 1997-02-05
- Date modifiied:
- 2019-04-23
Related products to: STIM1 Blocking Peptide
Related articles to: STIM1 Blocking Peptide
- In resting cells, STIM1, the dimeric endoplasmic reticulum (ER) Ca sensor that controls store-operated Ca entry (SOCE), is held in a Ca-bound inactive state by multiple intramolecular restraints, or brakes. Receptor-evoked release of Ca from the ER causes a large conformational change in STIM1 that releases the brakes and exposes the CRAC activation domain (CAD), enabling it to bind and open store-operated Orai1 channels in the plasma membrane. We performed single-molecule Förster resonance energy transfer (smFRET) measurements with purified STIM1 to better understand how Ca release from the luminal domain of STIM1 drives the conformational changes in the cytosolic domain that underlie CAD release. We find that Ca removal releases the CAD from CC1α1 (the "CC1 clamp") without obligatory formation of the CC1 coiled-coil that has been associated with CAD release in cells. Surprisingly, the CAD rearranges dramatically during release, as the two hairpin protomers that create its characteristic V-shaped structure are spread apart. Locking the two protomers together by cysteine crosslinking prevents CAD release, suggesting that the CAD must rearrange to escape the CC1 clamp. Our data support a model in which ER depletion-induced dimerization of the luminal SAM domains drives the cytosolic domain into multiple intermediate states including a 3-helix bundle of CC1α1/2/3, releasing the CC1 clamp and allowing the CAD to escape through a "fold-out" mechanism. Subsequent formation of the CC1 coiled-coil enables the CAD to revert to its original shape and extends it toward the plasma membrane to activate Orai1. - Source: PubMed
Publication date: 2026/08/18
Qiu RuoyiLewis Richard S - 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 - 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 - Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and remains a major unmet clinical challenge. Increasing evidence supports the view of HFpEF as a systemic inflammatory syndrome driven by aging and cardiometabolic comorbidities, including obesity, hypertension, and chronic kidney disease. Within this framework, regulatory T cells (Tregs), which are essential for maintaining immune tolerance and limiting excessive inflammation, have emerged as important modulators of disease progression. However, the mechanisms underlying Treg dysfunction in HFpEF have remained poorly understood. In this issue, Srinivas et al. identify stromal interaction molecule 1 (STIM1)-dependent calcium signaling as a critical regulator of Treg instability in HFpEF. The authors show that patients with HFpEF exhibit reduced circulating Treg numbers, increased STIM1 expression, and activation of endoplasmic reticulum stress, apoptotic, and inflammatory pathways. Using a cardiometabolic murine model and Treg-specific STIM1 knockout mice, they establish a causal role for Treg-intrinsic STIM1 signaling in disease development. These findings position STIM1 as a molecular link between cardiometabolic stress, immune dysregulation, and cardiac remodeling. They further support the concept that immune-cell plasticity is a major determinant of HFpEF pathogenesis and suggest that preserving Treg stability may represent a novel therapeutic strategy. Although important questions remain regarding disease timing, clinical translation, and sex-specific effects, this work advances our understanding of HFpEF as an immune-mediated disorder and identifies STIM1-dependent calcium signaling as a promising therapeutic target. - Source: PubMed
Publication date: 2026/08/01
Planavila AnnaBlasco-Roset Albert - Psoriasis is a chronic inflammatory skin disease driven by the synergistic interplay between aberrant epidermal proliferation and immune imbalance, with its core pathological process centered on the IL-23/IL-17 inflammatory axis. In recent years, accumulating evidence has demonstrated that calcium (Ca) signaling not only participates in keratinocyte (KC) differentiation and the maintenance of skin barrier homeostasis but also serves as a critical upstream regulator of the maturation and activation of immune cells, including dendritic cells (DCs), Th17 cells, neutrophils, and mast cells. This review systematically summarizes the mechanistic roles of Ca signaling dysregulation in psoriatic keratinocytes and multiple immune effector cells, with particular emphasis on the regulatory functions of SOCE within the DC-Th17 inflammatory axis. Current evidence indicates that the collapse of epidermal structural support systems, impaired Ca sensing, and SOCE dysfunction collectively contribute to insufficient local Ca signaling and defective KC differentiation. In contrast, persistently activated Ca-dependent signaling within the immune compartment promotes Th17 polarization, IL-17A release, and inflammatory cascade amplification through downstream pathways including Calcineurin-NFAT-RORγt. Based on these observations, this review further proposes that "compartment-specific bidirectional calcium dysregulation" may represent an underrecognized pathological pattern in psoriasis, characterized by the coexistence of impaired epidermal calcium signaling and persistent immune calcium hyperactivation. Furthermore, this review discusses therapeutic strategies targeting Ca signaling and their translational challenges, including SOCE-targeted interventions and future combinatorial therapeutic approaches. Overall, this review reappraises the pathogenesis of psoriasis from the perspective of Ca signaling with the aim of providing a novel theoretical basis for future precision immunomodulation and the development of innovative therapeutic strategies. - Source: PubMed
Publication date: 2026/07/15
Chen Y XZhuo D XWang F F