title: Multiple types of calcium channels arising from alternative translation initiation of the Orai1 message.
abstract: In mammals exclusively, the pore-forming Ca(2+) release-activated Ca(2+) (CRAC) channel subunit Orai1 occurs in two forms because of alternative translation initiation. The longer, mammal-specific Orai1α contains an additional 63 amino acids upstream of the conserved start site for Orai1β, which occurs at methionine 64 in Orai1α. Orai1 participates in the generation of three distinct Ca(2+) currents, including two store-operated currents: Icrac, which involves activation of Orai1 channels by the Ca(2+)-sensing protein STIM1 (stromal interaction molecule 1), and Isoc, which involves an interaction among Orai1, the transient receptor potential (TRP) family member TRPC1 (TRP canonical 1), and STIM1. Orai1 is also a pore-forming subunit of an arachidonic acid (or leukotriene C4)-regulated current Iarc that involves interactions among Orai1, Orai3, and STIM1. We evaluated the roles of the two Orai1 forms in the Ca(2+) currents Icrac, Isoc, and Iarc. We found that Orai1α and Orai1β were largely interchangeable for Icrac and Isoc, although Orai1α exhibited stronger inhibition by Ca(2+). Only the mammalian-specific Orai1α functioned in the arachidonic acid-regulated current Iarc. Thus, alternative translation initiation of the Orai1 message produces at least three types of Ca(2+) channels with distinct signaling and regulatory properties.
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
authors.forename: Pooja N
authors.initials: PN
authors.lastname: Desai
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
authors.forename: Xuexin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
authors.forename: Shilan
authors.initials: S
authors.lastname: Wu
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Janoshazi
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
authors.forename: Sunitha
authors.initials: S
authors.lastname: Bolimuntha
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA. putney@niehs.nih.gov mtrebak@hmc.psu.edu.
authors.forename: James W
authors.initials: JW
authors.lastname: Putney
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. putney@niehs.nih.gov mtrebak@hmc.psu.edu.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Trebak
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D015220:Calcium Channels / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D000071740:ORAI1 Protein; D010442:Peptide Chain Initiation, Translational / Q000187:drug effects / Q000502:physiology*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism
chemical_list: D015220:Calcium Channels; D000071740:ORAI1 Protein; C520430:Orai1 protein, mouse; D020033:Protein Isoforms; D012333:RNA, Messenger; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D016718:Arachidonic Acid