Divergence of Ca selectivity and equilibrium Ca blockade in a Ca release-activated Ca channel

Ca is a multifunctional signaling messenger crucial for diverse biological processes. Among the various ways by which cellular Ca signals are generated, storeoperated Ca release-activated Ca (CRAC) channels are recognized as a widespread mechanism for regulating transcription, motility, and proliferation in many cells (Feske, 2009; Hogan et al., 2010; Lewis, 2011). CRAC channels produce sustained intracellular Ca elevations and are implicated in a growing list of human diseases including immunodeficiency (Feske, 2009), allergy (Di Capite et al., 2011), cancer (Prevarskaya et al., 2011), thrombosis (Varga-Szabo et al., 2011), and inflammatory bowel disease (McCarl et al., 2010). The broad expression of CRAC channels and their involvement in many physiological processes has produced intense interest in CRAC channels as targets for drug development. Yet, our understanding of how CRAC channels operate at a mechanistic level is still rudimentary and, in particular, the molecular and structural mechanisms of ion permeation and channel gating are only now beginning to be elucidated.