Affiliations

Associate Professor, Physiology

Member, CTSI, Immunity, Microbes & Molecular Pathogenesis GPB Home Area, JCCC Signal Transduction and Therapeutics Program Area, Molecular, Cellular & Integrative Physiology GPB Home Area

Ca2+ signaling pathways are universally present and regulate processes ranging form cell differentiation to cell death. In many different cell types including the cells of the immune system, the depletion of intracellular endoplasmic reticulum Ca2+ stores by the receptor stimulation triggers Ca2+ entry through plasma membrane store-operated Ca2+ channels known as Ca2+ release-activated Ca2+ (CRAC) channels. The process of store-operated Ca2+ influx is critical for the immune responses in T cells as revealed by the pharmacological or knock-out mice studies targeting the well known downstream components of Ca2+ signaling pathway like NFAT (Nuclear Factor of Activated T cells) family of Ca2+-regulated transcription factors or calcineurin. Although the CRAC current was defined electrophysiologically in the early 80s���, the molecular identity of the CRAC channel stayed elusive till last year when we and other groups discovered the gene encoding a critical subunit of the CRAC channels. The gene was name by Dr. Gwack as Drosophila Orai (dOrai) and its mammalian homologues as Orai1, -2, -3. Dr. Gwack and colleagues used dual approach of genome-wide RNAi screen in Drosophila cells and a positional cloning method from human severe combined immune deficiency (SCID) patient cells to nail down Orai1 as the pore component of the CRAC channel. The importance of the CRAC channels was evident from the human SCID patients harboring single missense mutation in the coding sequence of Orai1 that abrogated store-operated Ca2+ influx in the T cells and fibroblasts of these patients. The identification of Orai for the first time gives us a molecular handle to study the macromolecular structure and mechanism of regulation of the CRAC channels. The long term objective of our research involves identification of the other components of the CRAC channel complex and development of possible therapeutic agents targeting the CRAC channels.