scholarly journals Orai1 regulates intracellular calcium, arrest, and shape polarization during neutrophil recruitment in shear flow

Blood ◽  
2010 ◽  
Vol 115 (3) ◽  
pp. 657-666 ◽  
Author(s):  
Ulrich Y. Schaff ◽  
Neha Dixit ◽  
Emily Procyk ◽  
Itsukyo Yamayoshi ◽  
Tiffany Tse ◽  
...  
Keyword(s):  
Shear Flow ◽  
Calcium Entry ◽  
Calcium Store ◽  
Immune Synapse ◽  
Acute Response ◽  
Formyl Peptide ◽  
Store Operated Calcium Entry ◽  
Cell Arrest ◽  
And Migration ◽  
Sirna Knockdown

Abstract Orai1 was reported to function as a calcium channel subunit that facilitates store operated calcium entry (SOCE) in T cells and is necessary for formation of the immune synapse. We reasoned that SOCE via Orai1 might regulate PMNs activation during recruitment to inflamed endothelium. Orai1 function was assessed by real-time imaging of calcium transients as PMNs were stimulated to roll, arrest, and migrate on E-selectin and ICAM-1 in shear flow. Calcium entry was significantly reduced when Orai1 function was impaired by heterozygous knockout in a mouse model or by siRNA knockdown in HL-60 cells. Reduced Orai-1 expression correlated with the delayed onset of arrest and reduced ability to transition to a polarized migratory phenotype. Inhibition of SOCE by treatment with 2-APB, or blocking phospholipase C (PLC) mediated calcium store release with U73122, abrogated formyl peptide induced calcium elevation, and delayed subsequent cell arrest and polarization. These results suggest that calcium entry via Orai1 is the predominant SOCE that cooperates with cytoplasmic calcium store release in coordinating integrin-dependent PMN arrest and migration in the acute response to inflammation.

scholarly journals A CRITICAL ROLE OF TRPC1-ORAI1-STIM1 MEDIATED STORE OPERATED CALCIUM ENTRY IN CARDIAC HYPERTROPHY

2015 ◽  
Vol 65 (10) ◽  
pp. A902
Author(s):  
Senthil Selvaraj ◽  
Brij Singh ◽  
Christian Bollensdorff ◽  
Jassim Al Suwaidi ◽  
Magdi Yacoub
Keyword(s):  
Cardiac Hypertrophy ◽  
Critical Role ◽  
Calcium Entry ◽  
Store Operated Calcium Entry

scholarly journals HGG-36. HIF-2: A NEW DRUG TARGET IN PEDIATRIC HIGH-GRADE GLIOMA WITH PROMISING PRECLINICAL RESULTS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii350-iii350
Author(s):  
Quentin Fuchs ◽  
Marina Pierrevelcin ◽  
Christophe Papin ◽  
Monique Dontenwill ◽  
Natacha Entz-Werlé
Keyword(s):  
Drug Testing ◽  
Treatment Resistance ◽  
High Grade Glioma ◽  
Clinical Work ◽  
Driver Mutations ◽  
High Grade ◽  
Innovative Strategy ◽  
Dismal Prognosis ◽  
Cell Arrest ◽  
And Migration

Abstract Pediatric high-grade gliomas (pHGGs) have a very dismal prognosis and need new innovative strategy for treatment. Despite the past discovery of histone H3 driver mutations, we are not able for instance to stop this induced epigenetic remodulation. Therefore, proactive translational studies wish to go further discovering new targetable proteins in pHGG. In our past clinical work, we were able to link significantly HIF-2alpha to a worse pHGG outcome and to their treatment resistance. We designed this new work to determine in several patient-derived cell lines (6 PDCLs) with or without H3.3 mutation the variation of HIF-2alpha, its role, its induction in normoxic and hypoxic microenvironment and its transcriptional targets using RNAseq, metabolomics and ChipSeq analyses. Complementary functional analyses were performed using siRNA strategy during cultures and migration assays. Finally, preclinical drug testing involving commercialized and non-commercialized HIF-2alpha specific inhibitors in the same PDCLs were evaluating their antiproliferative and pro-apoptotic effect. Our results confirmed the central role of HIF-2alpha in cell resistance to treatment, in pHGG stemness features and its direct link with metabolism adaptation and histone interaction. After the confirmation of its frequent presence in multiple PDCLs initiated from thalamic pHGGs and DIPG, we were using inhibitors in a single and combinatorial strategy targeting HIF-2alpha plus another hypoxia biomarker (mTor). This preclinical targeting was highly effective to favor cell arrest, apoptosis and to stop cell migration. In conclusion, HIF-2alpha seem to be a major biomarker in pHGGs that might be targeted giving a useful new opportunity for pHGG treatments.

scholarly journals Synthesis and Characterization of Store-Operated Calcium Entry Inhibitors Active in the Submicromolar Range

2020 ◽  
Vol 21 (24) ◽  
pp. 9777
Author(s):  
Camille Le Guilcher ◽  
Tomas Luyten ◽  
Jan B. Parys ◽  
Mathieu Pucheault ◽  
Olivier Dellis
Keyword(s):  
Cell Activation ◽  
Interleukin 2 ◽  
Calcium Entry ◽  
Ip3 Receptors ◽  
Excitable Cells ◽  
Cellular Targets ◽  
Entry Inhibitors ◽  
The Past ◽  
Store Operated Calcium Entry

The store-operated calcium entry, better known as SOCE, forms the main Ca2+ influx pathway in non-excitable cells, especially in leukocytes, where it is required for cell activation and the immune response. During the past decades, several inhibitors were developed, but they lack specificity or efficacy. From the non-specific SOCE inhibitor 2-aminoethyl diphenylborinate (2-APB), we synthetized 16 new analogues by replacing/modifying the phenyl groups. Among them, our compound P11 showed the best inhibitory capacity with a Ki ≈ 75 nM. Furthermore, below 1 µM, P11 was devoid of any inhibitory activity on the two other main cellular targets of 2-APB, the IP3 receptors, and the SERCA pumps. Interestingly, Jurkat T cells secrete interleukin-2 under phytohemagglutinin stimulation but undergo cell death and stop IL-2 synthesis when stimulated in the presence of increasing P11 concentrations. Thus, P11 could represent the first member of a new and potent family of immunosuppressors.

Store-operated calcium entry compensates fast ER calcium loss in resting hippocampal neurons

Cell Calcium ◽  
2015 ◽  
Vol 58 (2) ◽  
pp. 147-159 ◽  
Author(s):  
Samira Samtleben ◽  
Britta Wachter ◽  
Robert Blum
Keyword(s):  
Hippocampal Neurons ◽  
Calcium Entry ◽  
Store Operated Calcium Entry ◽  
Calcium Loss ◽  
Er Calcium
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