Calcium Release - Activated Calcium Current Icrac

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The prototypical store-operated calcium-influx pathway ICRAC (for “calcium-release activated calcium current”) originally was identified in Prof. Penner laboratory in 19921. Since then this lab, and others have acquired substantial information about ICRAC’s physiological and clinical importance, however, the molecular composition of the CRAC channels has remained elusive2. Only recently did a significant finding establish that a protein called stromal interaction molecule (STIM1), acting as the sensor for store Ca2+ content, is required for functional store-operated Ca2+ influx3, 4. This exciting finding was followed by the identification of another essential protein for store-operated calcium entry called CRAC Modulator 1 (CRACM1) by our group5 and Orai1 by an independent study from the Rao and Lewis laboratories6. Suppression of this protein by RNAi abolishes CRAC channel activity, as does a point mutation of CRACM1 in lymphocytes of some patients suffering from Severe Combined Immune Deficiency (SCID). The combined overexpression of STIM1 and CRACM1 greatly amplifies store-operated currents and these currents possess the most defining characteristics of ICRAC 7. Work from three laboratories (Cahalan, Rao, and our group) identified amino acids in transmembrane and loop domains of CRACM1 that affect ion selectivity, demonstrating that CRACM1 represents a pore-forming subunit of the CRAC channel. My data show that the CRACM1 homologs CRACM2 and CRACM38 also form store-operated channels with distinct properties. My proposal focuses on CRACM1 and its homologs, as a group of proteins that mediate store-operated Ca2+ entry with distinct functional properties. I propose biophysical, molecular and functional approaches to investigate the structural and mechanistic aspects of these proteins and their roles in store-operated Ca2+ entry.