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Defective STIM-mediated store operated Ca2+ entry in hepatocytes leads to metabolic dysfunction in obesity.

ABSTRACT: Defective Ca2+ handling is a key mechanism underlying hepatic endoplasmic reticulum (ER) dysfunction in obesity. ER Ca2+ level is in part monitored by the store-operated Ca2+ entry (SOCE) system, an adaptive mechanism that senses ER luminal Ca2+ concentrations through the STIM proteins and facilitates import of the ion from the extracellular space. Here, we show that hepatocytes from obese mice displayed significantly diminished SOCE as a result of impaired STIM1 translocation, which was associated with aberrant STIM1 O-GlycNAcylation. Primary hepatocytes deficient in STIM1 exhibited elevated cellular stress as well as impaired insulin action, increased glucose production and lipid droplet accumulation. Additionally, mice with acute liver deletion of STIM1 displayed systemic glucose intolerance. Conversely, over-expression of STIM1 in obese mice led to increased SOCE, which was sufficient to improve systemic glucose tolerance. These findings demonstrate that SOCE is an important mechanism for healthy hepatic Ca2+ balance and systemic metabolic control.

SUBMITTER: Arruda AP

PROVIDER: S-EPMC5777820 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Lysosomal agents inhibit store-operated Ca2+ entry.

Project description:Pharmacological manipulation of lysosome membrane integrity or ionic movements is a key strategy for probing lysosomal involvement in cellular processes. However, we have found an unexpected inhibition of store-operated Ca2+ entry (SOCE) by these agents. Dipeptides [glycyl-L-phenylalanine 2-naphthylamide (GPN) and L-leucyl-L-leucine methyl ester] that are inducers of lysosomal membrane permeabilization (LMP) uncoupled endoplasmic reticulum Ca2+-store depletion from SOCE by interfering with Stim1 oligomerization and/or Stim1 activation of Orai. Similarly, the K+/H+ ionophore, nigericin, that rapidly elevates lysosomal pH, also inhibited SOCE in a Stim1-dependent manner. In contrast, other strategies for manipulating lysosomes (bafilomycin A1, lysosomal re-positioning) had no effect upon SOCE. Finally, the effects of GPN on SOCE and Stim1 was reversed by a dynamin inhibitor, dynasore. Our data show that lysosomal agents not only release Ca2+ from stores but also uncouple this release from the normal recruitment of Ca2+ influx.

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Structural features of STIM and Orai underlying store-operated calcium entry.

Project description:Store-operated calcium entry (SOCE) through Orai channels is triggered by receptor-stimulated depletion of Ca2+ from the ER. Orai1 is unique in terms of its activation mechanism, biophysical properties, and structure, and its precise regulation is essential for human health. Recent studies have begun to reveal the structural basis of the major steps in the SOCE pathway and how the system is reliably suppressed in resting cells but able to respond robustly to ER Ca2+ depletion. In this review, we discuss current models describing the activation of ER Ca2+ sensor STIM1, its binding to Orai1, propagation of the binding signal from the channel periphery to the central pore, and the resulting conformational changes underlying opening of the highly Ca2+ selective Orai1 channel.

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Regulation of Store-Operated Ca2+ Entry by SARAF.

Project description:Calcium (Ca2+) signaling plays a dichotomous role in cellular biology, controlling cell survival and proliferation on the one hand and cellular toxicity and cell death on the other. Store-operated Ca2+ entry (SOCE) by CRAC channels represents a major pathway for Ca2+ entry in non-excitable cells. The CRAC channel has two key components, the endoplasmic reticulum Ca2+ sensor stromal interaction molecule (STIM) and the plasma-membrane Ca2+ channel Orai. Physical coupling between STIM and Orai opens the CRAC channel and the resulting Ca2+ flux is regulated by a negative feedback mechanism of slow Ca2+ dependent inactivation (SCDI). The identification of the SOCE-associated regulatory factor (SARAF) and investigations of its role in SCDI have led to new functional and molecular insights into how SOCE is controlled. In this review, we provide an overview of the functional and molecular mechanisms underlying SCDI and discuss how the interaction between SARAF, STIM1, and Orai1 shapes Ca2+ signaling in cells.

| S-EPMC8391525 | biostudies-literature

STIM1 regulates store-operated Ca2+ entry in oocytes.

Project description:The single transmembrane-spanning Ca(2+)-binding protein, STIM1, has been proposed to function as a Ca(2+) sensor that links the endoplasmic reticulum to the activation of store-operated Ca(2+) channels. In this study, the presence, subcellular localization and function of STIM1 in store-operated Ca(2+) entry in oocytes was investigated using the pig as a model. Cloning and sequence analysis revealed the presence of porcine STIM1 with a coding sequence of 2058 bp. In oocytes with full cytoplasmic Ca(2+) stores, STIM1 was localized predominantly in the inner cytoplasm as indicated by immunocytochemistry or overexpression of human STIM1 conjugated to the yellow fluorescent protein. Depletion of the Ca(2+) stores was associated with redistribution of STIM1 along the plasma membrane. Increasing STIM1 expression resulted in enhanced Ca(2+) influx after store depletion and subsequent Ca(2+) add-back; the influx was inhibited when the oocytes were pretreated with lanthanum, a specific inhibitor of store-operated Ca(2+) channels. When STIM1 expression was suppressed using siRNAs, there was no change in cytosolic free Ca(2+) levels in the store-depleted oocytes after Ca(2+) add-back. The findings suggest that in oocytes, STIM1 serves as a sensor of Ca(2+) store content that after store depletion moves to the plasma membrane to stimulate store-operated Ca(2+) entry.

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Numbers count: How STIM and Orai stoichiometry affect store-operated calcium entry.

Project description:Substantial progress has been made in the past several years in establishing the stoichiometries of STIM and Orai proteins and understanding their influence on store-operated calcium entry. Depletion of ER Ca2+ triggers STIM1 to accumulate at ER-plasma membrane junctions where it binds and opens Ca2+ release-activated Ca2+ (CRAC) channels. STIM1 is a dimer, and release of Ca2+ from its two luminal domains is reported to promote their association as well as drive formation of higher-order STIM1 oligomers. The CRAC channel, originally thought to be tetrameric, is now considered to be a hexamer of Orai1 subunits based on crystallographic and electrophysiological studies. STIM1 binding activates CRAC channels in a highly nonlinear way, such that all six Orai1 binding sites must be occupied to account for the activation and signature properties of native channels. The structural basis of STIM1 engagement with the channel is currently unclear, with evidence suggesting that STIM1 dimers bind to individual or pairs of Orai1 subunits. This review examines evidence that has led to points of consensus and debate about STIM1 and Orai1 stoichiometries, and explains the importance of STIM-Orai complex stoichiometry for the regulation of store-operated calcium entry.

| S-EPMC6461473 | biostudies-literature

Forms and functions of store-operated calcium entry mediators, STIM and Orai.

Project description:Calcium signals arise by multiple mechanisms, including mechanisms of release of intracellular stored Ca2+, and the influx of Ca2+ through channels in the plasma membrane. One mechanism that links these two sources of Ca2+ is store-operated Ca2+ entry, the most commonly encountered version of which involves the extensively studied calcium-release-activated Ca2+ (CRAC) channel. The minimal and essential molecular components of the CRAC channel are the STIM proteins that function as Ca2+ sensors in the endoplasmic reticulum, and the Orai proteins that comprise the pore forming subunits of the CRAC channel. CRAC channels are known to play significant roles in a wide variety of physiological functions. This review discusses the multiple forms of STIM and Orai proteins encountered in mammalian cells, and discusses some specific examples of how these proteins modulate or mediate important physiological processes.

| S-EPMC5955777 | biostudies-literature

S-acylation of Orai1 regulates store-operated Ca2+ entry.

Project description:Store-operated Ca2+ entry is a central component of intracellular Ca2+ signaling pathways. The Ca2+ release-activated channel (CRAC) mediates store-operated Ca2+ entry in many different cell types. The CRAC channel is composed of the plasma membrane (PM)-localized Orai1 channel and endoplasmic reticulum (ER)-localized STIM1 Ca2+ sensor. Upon ER Ca2+ store depletion, Orai1 and STIM1 form complexes at ER-PM junctions, leading to the formation of activated CRAC channels. Although the importance of CRAC channels is well described, the underlying mechanisms that regulate the recruitment of Orai1 to ER-PM junctions are not fully understood. Here, we describe the rapid and transient S-acylation of Orai1. Using biochemical approaches, we show that Orai1 is rapidly S-acylated at cysteine 143 upon ER Ca2+ store depletion. Importantly, S-acylation of cysteine 143 is required for Orai1-mediated Ca2+ entry and recruitment to STIM1 puncta. We conclude that store depletion-induced S-acylation of Orai1 is necessary for recruitment to ER-PM junctions, subsequent binding to STIM1 and channel activation.

| S-EPMC8255033 | biostudies-literature

Attenuated mesangial cell proliferation related to store-operated Ca2+ entry in aged rat: the role of STIM 1 and Orai 1.

Project description:Store-operated Ca(2+) entry (SOCE) is a common and ubiquitous mechanism regulating Ca(2+) influx into cells and participates in numerous biological processes including cell proliferation. Glomerular mesangial cells (GMCs) play a role in the regulation of the glomerular filtration rate. From a clinical point of view, many physiological functions alter with age. In the present study, we used angiotensin II, glucagon, and the sarco/endoplasmic reticulum membrane Ca(2+) pump inhibitor thapsigargin to deplete the internal Ca(2+) stores for the activation of SOCE. We found that SOCE was significantly attenuated in GMCs from aged (22-month-old) rats. The expression of SOCE-related components, stromal interaction molecule 1 (STIM 1) and Orai 1, in freshly isolated glomeruli notably decreased, and STIM 1 and Orai 1 puncta formation significantly reduced in primary-cultured GMCs in aged rats. Moreover, specific knockdown of STIM 1 and Orai 1 by small interfering RNA markedly suppressed SOCE and cell proliferation of GMCs isolated from young (3-month-old) rats. We conclude that the attenuation of GMCs proliferation can be attributed to the decreased SOCE partially caused by reduced expression of STIM 1 and Orai 1.

| S-EPMC3824990 | biostudies-literature

Defective Store-Operated Calcium Entry Causes Partial Nephrogenic Diabetes Insipidus.

Project description:Store-operated calcium entry (SOCE) is the mechanism by which extracellular signals elicit prolonged intracellular calcium elevation to drive changes in fundamental cellular processes. Here, we investigated the role of SOCE in the regulation of renal water reabsorption, using the inbred rat strain SHR-A3 as an animal model with disrupted SOCE. We found that SHR-A3, but not SHR-B2, have a novel truncating mutation in the gene encoding stromal interaction molecule 1 (STIM1), the endoplasmic reticulum calcium (Ca(2+)) sensor that triggers SOCE. Balance studies revealed increased urine volume, hypertonic plasma, polydipsia, and impaired urinary concentrating ability accompanied by elevated circulating arginine vasopressin (AVP) levels in SHR-A3 compared with SHR-B2. Isolated, split-open collecting ducts (CD) from SHR-A3 displayed decreased basal intracellular Ca(2+) levels and a major defect in SOCE. Consequently, AVP failed to induce the sustained intracellular Ca(2+) mobilization that requires SOCE in CD cells from SHR-A3. This effect decreased the abundance of aquaporin 2 and enhanced its intracellular retention, suggesting impaired sensitivity of the CD to AVP in SHR-A3. Stim1 knockdown in cultured mpkCCDc14 cells reduced SOCE and basal intracellular Ca(2+) levels and prevented AVP-induced translocation of aquaporin 2, further suggesting the effects in SHR-A3 result from the expression of truncated STIM1. Overall, these results identify a novel mechanism of nephrogenic diabetes insipidus and uncover a role of SOCE in renal water handling.

| S-EPMC4926963 | biostudies-literature

Store operated Ca2+ entry (SOCE) controls ameloblast cell function and enamel development

Project description:Abstarct:Mutations in the endoplasmic reticulum (ER) Ca2+ sensor stromal interaction molecule 1 (STIM1) result is a number of disease states including abnormal enamel formation. However, these defects in enamel have remained unclear given a lack of animal models available. We generated Stim1/2K14Cre mice to ablate the activity of STIM1 and its homologue STIM2 in enamel cells. These mice showed impaired Ca2+ entry in enamel cells and although enamel formed, it was severely hypomineralized and mechanically weak. RNA-sequencing of enamel cells provided a global overview of loss of Ca2+ sensor activity. ER stress markers associated with unfolded protein response (UPR) were increased. Cell morphology was altered showing loss of the typical ruffled-border and mislocalized mitochondria. We also identified decreased glutathione system and potentially associated with this, increased ROS and abnormal mitochondria. The Ca2+ extrusion system and enamel gene expression were also altered. These data might represent the first in vivo study linking Stim1/2 ablation with increased UPR function, decreased glutathione metabolism, increased ROS and abnormal mitochondria. Loss of ER Ca2+ sensors Stim1/2 in enamel cells has substantial detrimental effects at the cell and mineral phase level.

2017-01-17 | GSE93655 | GEO

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