Neuronal store-operated calcium entry pathway as a novel therapeutic target for Huntington's disease treatment.
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ABSTRACT:
SUBMITTER: Wu J
PROVIDER: S-EPMC3124661 | biostudies-literature | 2011 Jun
REPOSITORIES: biostudies-literature
Publications
Neuronal store-operated calcium entry pathway as a novel therapeutic target for Huntington's disease treatment.
Wu Jun J Shih Hsin-Pei HP Vigont Vladimir V Hrdlicka Lori L Diggins Len L Singh Carol C Mahoney Matt M Chesworth Richard R Shapiro Gideon G Zimina Olga O Chen Xuesong X Wu Qingqing Q Glushankova Lyubov L Ahlijanian Michael M Koenig Gerhard G Mozhayeva Galina N GN Kaznacheyeva Elena E Bezprozvanny Ilya I
Chemistry & biology 20110601 6
Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine expansion within Huntingtin (Htt) protein. In the phenotypic screen we identified a class of quinazoline-derived compounds that delayed a progression of a motor phenotype in transgenic Drosophila HD flies. We found that the store-operated calcium (Ca(2+)) entry (SOC) pathway activity is enhanced in neuronal cells expressing mutant Htt and that the identified compounds inhibit SOC pathway in HD neurons. The same c ...[more]
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Project description:Calcium influx through plasma membrane ion channels is crucial for many events in cellular physiology. Cell surface stimuli lead to the production of inositol 1,4,5-trisphosphate (IP3), which binds to IP3 receptors (IP3R) in the endoplasmic reticulum (ER) to release calcium pools from the ER lumen. This leads to the depletion of ER calcium pools, which has been termed store depletion. Store depletion leads to the dissociation of calcium ions from the EF-hand motif of the ER calcium sensor Stromal Interaction Molecule 1 (STIM1). This leads to a conformational change in STIM1, which helps it to interact with the plasma membrane (PM) at ER:PM junctions. At these ER:PM junctions, STIM1 binds to and activates a calcium channel known as Orai1 to form calcium release-activated calcium (CRAC) channels. Activation of Orai1 leads to calcium influx, known as store-operated calcium entry (SOCE). In addition to Orai1 and STIM1, the homologs of Orai1 and STIM1, such as Orai2/3 and STIM2, also play a crucial role in calcium homeostasis. The influx of calcium through the Orai channel activates a calcium current that has been termed the CRAC current. CRAC channels form multimers and cluster together in large macromolecular assemblies termed "puncta". How CRAC channels form puncta has been contentious since their discovery. In this review, we will outline the history of SOCE, the molecular players involved in this process, as well as the models that have been proposed to explain this critical mechanism in cellular physiology.
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Project description:Cellular homeostasis relies upon precise regulation of Ca(2+) concentration. Stromal interaction molecule (STIM) proteins regulate store-operated calcium entry (SOCE) by sensing Ca(2+) concentration in the ER and forming oligomers to trigger Ca(2+) entry through plasma membrane-localized Orai1 channels. Here we characterize a STIM2 splice variant, STIM2.1, which retains an additional exon within the region encoding the channel-activating domain. Expression of STIM2.1 is ubiquitous but its abundance relative to the more common STIM2.2 variant is dependent upon cell type and highest in naive T cells. STIM2.1 knockdown increases SOCE in naive CD4(+) T cells, whereas knockdown of STIM2.2 decreases SOCE. Conversely, overexpression of STIM2.1, but not STIM2.2, decreases SOCE, indicating its inhibitory role. STIM2.1 interaction with Orai1 is impaired and prevents Orai1 activation, but STIM2.1 shows increased affinity towards calmodulin. Our results imply STIM2.1 as an additional player tuning Orai1 activation in vivo.
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Project description:Calcium entry from the extracellular space into cells is an important signaling mechanism in both physiological and pathophysiological functions. In non-excitable cells, store-operated calcium (SOC) entry represents a principal mode of calcium entry. Activation of SOC entry in pulmonary artery endothelial cells leads to the formation of inter-endothelial cell gaps and subsequent endothelial barrier disruption. Regulation of endothelial SOC entry is poorly understood. In this work, we identify two large molecular weight immunophilins, FKBP51 and FKBP52, as novel regulators of SOC entry in endothelial cells. Using cell fractionation studies and immunocytochemistry we determined that a fraction of these largely cytosolic proteins localize to the plasma membrane where SOC entry channels are found. That FKBP51 and FKBP52 associate with SOC entry channel protein complexes was supported by co-precipitation of the immunophilins with TRPC4, a subunit of the calcium-selective, SOC entry channel ISOC. Dexamethasone-induced upregulation of FKBP51 expression in pulmonary artery endothelial cells reduced global SOC entry as well as ISOC. Similar results were observed when FKBP51 was over-expressed in an inducible HEK293 cell line. On the other hand, when FKBP52 was over-expressed SOC entry was enhanced. When expression of FKBP52 was inhibited, SOC entry was decreased. Collectively, our observations support regulatory roles for these large molecular weight immunophilins in which FKBP51 inhibits, whereas FKBP52 enhances, SOC entry in endothelial cells.
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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.
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Project description:Our previous study demonstrated that the abundance of extracellular matrix proteins was suppressed by store-operated Ca2+ entry (SOCE) in mesangial cells (MCs). The present study was conducted to investigate the underlying mechanism focused on the transforming growth factor-β1 (TGF-β1)/Smad3 pathway, a critical pathway for ECM expansion in diabetic kidneys. We hypothesized that SOCE suppressed ECM protein expression by inhibiting this pathway in MCs. In cultured human MCs, we observed that TGF-β1 (5 ng/ml for 15 h) significantly increased Smad3 phosphorylation, as evaluated by immunoblot. However, this response was markedly inhibited by thapsigargin (1 µM), a classical activator of store-operated Ca2+ channels. Consistently, both immunocytochemistry and immunoblot showed that TGF-β1 significantly increased nuclear translocation of Smad3, which was prevented by pretreatment with thapsigargin. Importantly, the thapsigargin effect was reversed by lanthanum (La3+; 5 µM) and GSK-7975A (10 µM), both of which are selective blockers of store-operated Ca2+ channels. Furthermore, knockdown of Orai1, the pore-forming subunit of the store-operated Ca2+ channels, significantly augmented TGF-β1-induced Smad3 phosphorylation. Overexpression of Orai1 augmented the inhibitory effect of thapsigargin on TGF-β1-induced phosphorylation of Smad3. In agreement with the data from cultured MCs, in vivo knockdown of Orai1 specific to MCs using a targeted nanoparticle small interfering RNA delivery system resulted in a marked increase in abundance of phosphorylated Smad3 and in nuclear translocation of Smad3 in the glomerulus of mice. Taken together, our results indicate that SOCE in MCs negatively regulates the TGF-β1/Smad3 signaling pathway.
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Project description:Neurodegenerative pathologies are among the most serious and socially significant problems of modern medicine, along with cardiovascular and oncological diseases. Several attempts have been made to prevent neuronal death using novel drugs targeted to the cell calcium signaling machinery, but the lack of adequate models for screening markedly impairs the development of relevant drugs. A potential breakthrough in this field is offered by the models of hereditary neurodegenerative pathologies based on endogenous expression of mutant proteins in neurons differentiated from patient-specific induced pluripotent stem cells (iPSCs). Here, we study specific features of store-operated calcium entry (SOCE) using an iPSCs-based model of Huntington's disease (HD) and analyze the pharmacological effects of a specific drug targeted to the calcium channels. We show that SOCE in gamma aminobutyric acid-ergic striatal medium spiny neurons (GABA MSNs) was mediated by currents through at least two different channel groups, ICRAC and ISOC. Both of these groups were upregulated in HD neurons compared with the wild-type neurons. Thapsigargin-induced intracellular calcium store depletion in GABA MSNs resulted in predominant activation of either ICRAC or ISOC. The potential anti-HD drug EVP4593, which was previously shown to have neuroprotective activity in different HD models, affected both ICRAC and ISOC.
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