In many different cell types including the cells of the immune system, the depletion of intracellular endoplasmic
reticulum Ca2+ stores by receptor stimulation triggers Ca2+ entry through plasma membrane store-operated Ca2+ channels
known as Ca2+ release-activated Ca2+ (CRAC) channels. 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 two other
groups discovered the gene encoding a critical subunit of the CRAC channels. The gene was named by me as Drosophila Orai
(dOrai) and its mammalian homologues as Orai1, -2, -3 after discovery by genome-wide RNAi screen in Drosophila cells.
The identification of Orai for the first time gives us a molecular handle to study the macromolecular structure and
mechanism of regulation of CRAC channels. Presently we are analyzing the phenotype of Orai1 knock out mice to understand
the physiological role of the CRAC channel function in the immune system and in the long term in other cell types where
Ca2+/Calcineurin/NFAT signaling is known to play an important role.
Schematic diagram showing two phases of activation of store-operated
Ca2+ entry in T cells. The ER Ca2+ store is depleted by IP3 produced by PLC-gamma activated through the
ligand-receptor engagement (Phase 1). The depletion can trigger opening of the CRAC channels on the plasma membrane
(Phase 2). The long sought genes encoding the CRAC channel component was found by genome-wide RNAi screen
(Nature, 441, p179) and named as “Orai”.
Srikanth S, Jew M, Kim KD, Yee MK, Abramson J, Gwack Y. (2012) Junctate is a Ca2+-sensing structural component of Orai1 and STIM1 clustering site at the proximal plasma membrane. PNAS May 29; 109(22):8682-7.
Srikanth S, Jung HJ, Kim KD, Souda P, Whitelegge JP, Gwack Y. (2010) A novel EF hand-containing protein, CRACR2A is a cytosolic Ca2+ sensor that stabilizes active conformation of the CRAC channel. Nature Cell Biology (article) May; 12(5): 436-446.
Feske S*, Gwack Y*, Prakriya M, Srikanth S, Puppel S-H, Tanasa B, Hogan PG, Lewis RS, Daly M, Rao A. (2006) A mutation in Orai1 causes immune deficiency by abrogating store-operated Ca2+ entry and CRAC channel function. Nature (Article) May 11;441(7090):179-85. (*-equal Contribution).
Link to my complete PubMed bibliography: