Molecular basis of the CRAC channel

Abstract

Ca 2+ release-activated Ca 2+ (CRAC) channels, located in the plasma membrane, are opened upon release of Ca 2+ from intracellular stores, permitting Ca 2+ entry and sustained [Ca 2+ ] i signaling that replenishes the store in numerous cell types. This mechanism is particularly important in T lymphocytes of the immune system, providing the missing link in the signal transduction cascade that is initiated by T cell receptor engagement and leads to altered expression of genes that results ultimately in the production of cytokines and cell proliferation. In the past three years, RNA interference screens together with over-expression and site-directed mutagenesis have identified the triggering molecule (Stim) that links store depletion to CRAC channel-mediated Ca 2+ influx and the pore subunit (Orai) of the CRAC channel that allows highly selective entry of Ca 2+ ions into cells.

Dynamic Movement of the Calcium Sensor STIM1 and the Calcium Channel Orai1 in Activated T-Cells: Puncta and Distal Caps

“…Although sustained Ca 2ϩ influx in T-cells has been studied for decades, the proteins involved have only been identified recently (Cahalan et al, 2007;Feske, 2007;Gwack et al, 2007a;Hewavitharana et al, 2007;Hogan and Rao, 2007;Lewis, 2007;Putney, 2007b). Stromal-interacting molecule (STIM) was identified as an essential component for Ca 2ϩ influx through CRAC channels by RNA interference (RNAi) screens in Drosophila and HeLa cells (Liou et al, 2005;Roos et al, 2005).…”

“…The depletion of Ca 2ϩ from this internal store then leads to the opening of ion channels in the plasma membrane (PM) allowing an influx of Ca 2ϩ from outside the cell. The store-operated channel responsible for Ca 2ϩ influx in T-cells is known as the Ca 2ϩ release-activated Ca 2ϩ (CRAC) channel, which has been studied by electrophysiological techniques for many years (Lewis, 2001;Prakriya and Lewis, 2003;Cahalan et al, 2007;Hewavitharana et al, 2007;Hogan and Rao, 2007;Putney, 2007a).…”

“…In particular, elevated Ca 2ϩ maintains prolonged nuclear accumulation of nuclear factor of activated T-cells (NFAT) by activating the phosphatase calcineurin that dephosphorylates NFAT, allowing it to translocate to the nucleus and activate genes such as IL2 (Hogan et al, 2003;Macian, 2005). Several hours of Ca 2ϩ influx are required to complete the T-cell activation program, which involves expression of a large number of activation-associated genes (Lewis, 2001;Macian et al, 2002;Hogan et al, 2003).Although sustained Ca 2ϩ influx in T-cells has been studied for decades, the proteins involved have only been identified recently (Cahalan et al, 2007;Feske, 2007;Gwack et al, 2007a;Hewavitharana et al, 2007;Hogan and Rao, 2007;Lewis, 2007;Putney, 2007b). Stromal-interacting molecule (STIM) was identified as an essential component for Ca 2ϩ influx through CRAC channels by RNA interference (RNAi) screens in Drosophila and HeLa cells (Liou et al, 2005;Roos et al, 2005 Abbreviations used: APC, antigen-presenting cell; CRAC, Ca 2ϩ release-activated Ca 2ϩ channel; ER, endoplasmic reticulum; FRAP, fluorescence recovery after photobleaching; FRET, Fö rster resonance energy transfer; IS, immunological synapse; MEF, mouse embryonic fibroblast; PM, plasma membrane; TCR, T-cell receptor.…”

“…The depletion of Ca 2ϩ from this internal store then leads to the opening of ion channels in the plasma membrane (PM) allowing an influx of Ca 2ϩ from outside the cell. The store-operated channel responsible for Ca 2ϩ influx in T-cells is known as the Ca 2ϩ release-activated Ca 2ϩ (CRAC) channel, which has been studied by electrophysiological techniques for many years (Lewis, 2001;Prakriya and Lewis, 2003;Cahalan et al, 2007;Hewavitharana et al, 2007;Hogan and Rao, 2007;Putney, 2007a).Sustained elevation of cytosolic Ca 2ϩ is required for complete T-cell activation (Iezzi et al, 1998;Lewis, 2001;Hogan et al, 2003;Feske, 2007). High levels of intracellular Ca 2ϩ are necessary to maintain the interaction between a T-cell and antigen-presenting cell (APC) that leads to formation of the specialized contact surface known as the immunological synapse (IS).…”

Store-Operated Calcium Channels: New Perspectives on Mechanism and Function

“…The discoveries of the ER Ca 2þ sensor STIM1 in 2005 and the CRAC channel protein Orai1 a year later marked an unmistakable turning point in the field, as they provided the first and most essential molecular tools with which to dissect the SOCE mechanism. The history of these discoveries and the early revelations they afforded have been reviewed extensively (Cahalan et al 2007;Wu et al 2007;Fahrner et al 2009;Putney 2009;Várnai et al 2009;Hogan et al 2010). In this review, I will summarize our current understanding of how Ca 2þ store depletion leads to Ca 2þ entry at a molecular level, and the role of STIM oligomerization and additional proteins in this process.…”