{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:26:41Z","timestamp":1785130001088,"version":"3.55.0"},"reference-count":45,"publisher":"Wiley","issue":"22","license":[{"start":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:00:00Z","timestamp":1666137600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007458","name":"Qatar Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007458","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008982","name":"Qatar National Research Fund","doi-asserted-by":"publisher","award":["NPRP12S\u20100212\u2010190074"],"award-info":[{"award-number":["NPRP12S\u20100212\u2010190074"]}],"id":[{"id":"10.13039\/100008982","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Loss of function mutations in store\u2010operated Ca<jats:sup>2+<\/jats:sup> entry (SOCE) are associated with severe paediatric disorders in humans, including combined immunodeficiency, anaemia, thrombocytopenia, anhidrosis and muscle hypotonia. Given its central role in immune cell activation, SOCE has been a therapeutic target for autoimmune and inflammatory diseases. Treatment for such chronic diseases would require prolonged SOCE inhibition. It is, however, unclear whether chronic SOCE inhibition is viable therapeutically. Here we address this issue using a novel genetic mouse model (SOCE hypomorph) with deficient SOCE, nuclear factor of activated T cells activation, and T cell cytokine production. SOCE hypomorph mice develop and reproduce normally and do not display muscle weakness or overt anhidrosis. They do, however, develop cardiovascular complications, including hypertension and tachycardia, which we show are due to increased sympathetic autonomic nervous system activity and not cardiac or vascular smooth muscle autonomous defects. These results assert that chronic SOCE inhibition is viable therapeutically if the cardiovascular complications can be managed effectively clinically. They further establish the SOCE hypomorph line as a genetic model to define the therapeutic window of SOCE inhibition and dissect toxicities associated with chronic SOCE inhibition in a tissue\u2010specific fashion.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15294-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>A floxed stromal interaction molecule 1 (STIM1)\u00a0hypomorph mouse model was generated with significant reduction in Ca<jats:sup>2+<\/jats:sup> influx through store\u2010operated Ca<jats:sup>2+<\/jats:sup> entry (SOCE), resulting in defective nuclear translocation of nuclear factor of activated T cells, cytokine production and inflammatory response. The hypomorph mice are viable and fertile, with no overt defects.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Decreased SOCE in the hypomorph mice is due to poor translocation of the mutant STIM1 to endoplasmic reticulum\u2013plasma membrane contact sites resulting in fewer STIM1 puncta.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Hypomorph mice have similar susceptibility to controls to develop diabetes but exhibit tachycardia and hypertension. The hypertension is not due to increased vascular smooth muscle contractility or vascular remodelling.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The tachycardia is not due to heart\u2010specific defects but rather seems to be due to increased circulating catecholamines in the hypomorph.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Therefore, long term SOCE inhibition is viable if the cardiovascular defects can be managed clinically.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp283811","type":"journal-article","created":{"date-parts":[[2022,10,1]],"date-time":"2022-10-01T13:03:20Z","timestamp":1664629400000},"page":"4827-4848","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Chronic reduction of store operated Ca<sup>2+<\/sup> entry is viable therapeutically but is associated with cardiovascular complications"],"prefix":"10.1113","volume":"600","author":[{"given":"Fang","family":"Yu","sequence":"first","affiliation":[{"name":"Calcium Signaling Group Research Department Weill Cornell Medicine Qatar Education City Qatar Foundation  Doha Qatar"},{"name":"Department of Physiology and Biophysics Weill Cornell Medicine  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Courjaret","sequence":"additional","affiliation":[{"name":"Calcium Signaling Group Research Department Weill Cornell Medicine Qatar Education City Qatar Foundation  Doha Qatar"},{"name":"Department of Physiology and Biophysics Weill Cornell Medicine  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asha","family":"Elmi","sequence":"additional","affiliation":[{"name":"College of Health and Life Science Hamad bin Khalifa University  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethel 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