A new selective pharmacological enhancer of the Orai1 Ca2+ channel reveals roles for Orai1 in smooth and skeletal muscle functions.

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dc.contributor.author Azimi, Iman
dc.contributor.author Stevenson, Ralph J
dc.contributor.author Zhang, Xuexin
dc.contributor.author Meizoso-Huesca, Aldo
dc.contributor.author Xin, Ping
dc.contributor.author Johnson, Martin
dc.contributor.author Flanagan, Jack U
dc.contributor.author Chalmers, Silke B
dc.contributor.author Yoast, Ryan E
dc.contributor.author Kapure, Jeevak S
dc.contributor.author Ross, Benjamin P
dc.contributor.author Vetter, Irina
dc.contributor.author Ashton, Mark R
dc.contributor.author Launikonis, Bradley S
dc.contributor.author Denny, William A
dc.contributor.author Trebak, Mohamed
dc.contributor.author Monteith, Gregory R
dc.coverage.spatial United States
dc.date.accessioned 2022-02-03T00:53:33Z
dc.date.available 2022-02-03T00:53:33Z
dc.date.issued 2020-2
dc.identifier.citation ACS pharmacology & translational science 3(1):135-147 Feb 2020
dc.identifier.issn 2575-9108
dc.identifier.uri https://hdl.handle.net/2292/58103
dc.description.abstract Store operated calcium (Ca2+) entry is an important homeostatic mechanism in cells, whereby the release of Ca2+ from intracellular endoplasmic reticulum stores triggers the activation of a Ca2+ influx pathway. Mediated by Orai1, this Ca2+ influx has specific and essential roles in biological processes as diverse as lactation to immunity. Although pharmacological inhibitors of this Ca2+ influx mechanism have helped to define the role of store operated Ca2+ entry in many cellular events, the lack of isoform specific modulators and activators of Orai1 has limited our full understanding of these processes. Here we report the identification and synthesis of an Orai1 activity enhancer that concurrently potentiated Orai1 Ca2+ -dependent inactivation (CDI). This unique enhancer of Orai1 had only a modest effect on Orai3 with weak inhibitory effects at high concentrations in intact MCF-7 breast cancer cells. The Orai1 enhancer heightened vascular smooth muscle cell migration induced by platelet-derived growth factor and the unique store operated Ca2+ entry pathway present in skeletal muscle cells. These studies show that IA65 is an exemplar for the translation and development of Orai isoform selective agents. The ability of IA65 to activate CDI demonstrates that agents can be developed that can enhance Orai1-mediated Ca2+ influx but avoid the cytotoxicity associated with sustained Orai1 activation. IA65 and/or future analogues with similar Orai1 and CDI activating properties could be fine tuners of physiological processes important in specific disease states, such as cellular migration and immune cell function.
dc.format.medium Print-Electronic
dc.language eng
dc.publisher American Chemical Society (ACS)
dc.relation.ispartofseries ACS pharmacology & translational science
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm
dc.rights.uri https://pubs.acs.org/page/policy/authorchoice_termsofuse.html
dc.subject Ca2+ influx
dc.subject Orai1
dc.subject enhancer
dc.subject skeletal muscle
dc.subject smooth muscle
dc.subject Science & Technology
dc.subject Life Sciences & Biomedicine
dc.subject Chemistry, Medicinal
dc.subject Pharmacology & Pharmacy
dc.subject Orai1
dc.subject Ca2+ influx
dc.subject enhancer
dc.subject smooth muscle
dc.subject skeletal muscle
dc.subject BREAST-CANCER
dc.subject I-CRAC
dc.subject STORE
dc.subject ENTRY
dc.subject FIBERS
dc.subject INHIBITORS
dc.subject EXCITATION
dc.title A new selective pharmacological enhancer of the Orai1 Ca2+ channel reveals roles for Orai1 in smooth and skeletal muscle functions.
dc.type Journal Article
dc.identifier.doi 10.1021/acsptsci.9b00081
pubs.issue 1
pubs.begin-page 135
pubs.volume 3
dc.date.updated 2022-01-10T00:54:18Z
dc.rights.holder Copyright: 2020 American Chemical Society en
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/32190822
pubs.end-page 147
pubs.publication-status Published
dc.rights.accessrights http://purl.org/eprint/accessRights/OpenAccess en
pubs.subtype research-article
pubs.subtype Journal Article
pubs.elements-id 810298
dc.identifier.eissn 2575-9108
pubs.online-publication-date 2020-1-13

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