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Using high-throughput chemical library screening targeting Orai1, we identified a novel class of small molecules that inhibit CRAC channel activity. One of these molecules, compound 5D, inhibited CRAC channel activity by blocking ion permeation. When included during differentiation, Th17 cells showed higher sensitivity to compound 5D than Th1 and Th2 cells. The selectivity was attributable to high dependence of promoters of retinoic-acid-receptor-related orphan receptors on the Ca2+-NFAT pathway. Blocking of CRAC channels drastically decreased recruitment of NFAT and histone modifications within key gene loci involved in Th17 differentiation. The impairment in Th17 differentiation by treatment with CRAC channel blocker was recapitulated in Orai1-deficient T cells, which could be rescued by exogenous expression of retinoic-acid-receptor-related orphan receptors or a constitutive active mutant of NFAT. In vivo administration of CRAC channel blockers effectively reduced the severity of experimental autoimmune encephalomyelitis by suppression of differentiation of inflammatory T cells. These results suggest that CRAC channel blockers can be considered as chemical templates for the development of therapeutic agents to suppress inflammatory responses.<\/jats:p>","DOI":"10.4049\/jimmunol.1302586","type":"journal-article","created":{"date-parts":[[2013,12,5]],"date-time":"2013-12-05T03:03:00Z","timestamp":1386212580000},"page":"110-122","source":"Crossref","is-referenced-by-count":77,"title":["Calcium Signaling via Orai1 Is Essential for Induction of the Nuclear Orphan Receptor Pathway To Drive Th17 Differentiation"],"prefix":"10.1093","volume":"192","author":[{"given":"Kyun-Do","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Physiology, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonal","family":"Srikanth","sequence":"additional","affiliation":[{"name":"Department of Physiology, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yossan-Var","family":"Tan","sequence":"additional","affiliation":[{"name":"Semel Institute\/Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma-Khin","family":"Yee","sequence":"additional","affiliation":[{"name":"Department of Physiology, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Jew","sequence":"additional","affiliation":[{"name":"Department of Physiology, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Damoiseaux","sequence":"additional","affiliation":[{"name":"California Nanosystems Institute, University of California Los Angeles , Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California Los Angeles , Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saki","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Division of Hematology-Oncology, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, CA 90095"},{"name":"University of California Los Angeles AIDS Institute , Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Sung","family":"An","sequence":"additional","affiliation":[{"name":"Division of Hematology-Oncology, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, CA 90095"},{"name":"University of California Los Angeles AIDS Institute , Los Angeles, CA 90095"},{"name":"University of California Los Angeles School of Nursing , Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Ribalet","sequence":"additional","affiliation":[{"name":"Department of Physiology, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A","family":"Waschek","sequence":"additional","affiliation":[{"name":"Semel Institute\/Department of Psychiatry, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yousang","family":"Gwack","sequence":"additional","affiliation":[{"name":"Department of Physiology, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,1,1]]},"reference":[{"key":"2025032404050846500_r1","doi-asserted-by":"crossref","first-page":"a003970","DOI":"10.1101\/cshperspect.a003970","article-title":"Store-operated calcium channels: new perspectives on mechanism and function","volume":"3","author":"Lewis","year":"2011","journal-title":"Cold Spring Harb. 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