Structural and Functional Mechanisms of CRAC Channel Regulation

In many animal cells, stimulation of cell surface receptors coupled to G proteins or tyrosine kinases mobilizes Ca2 + influx through store-operated Ca2+-release-activated Ca2 + (CRAC) channels. The ensuing Ca2 + entry regulates a wide variety of effector cell responses including transcription, motility, and proliferation. The physiological importance of CRAC channels for human health is underscored by studies indicating that mutations in CRAC channel genes produce a spectrum of devastating diseases including chronic inflammation, muscle weakness, and a severe combined immunodeficiency syndrome. Moreover, from a basic science perspective, CRAC channels exhibit a unique biophysical fingerprint characterized by exquisite Ca2 + selectivity, store-operated gating, and distinct pore properties and therefore serve as fascinating model ion channels for understanding the biophysical mechanisms of Ca2+ selectivity and channel opening. Studies in the last two decades have revealed the cellular and molecular choreography of the CRAC channel activation process, and it is now established that opening of CRAC channels is governed through direct interactions between the pore-forming Orai proteins and the endoplasmic reticulum Ca2 + sensors STIM1 and STIM2. In this review, we summarize the functional and structural mechanisms of CRAC channel regulation, focusing on recent advances in our understanding of the conformational and structural dynamics of CRAC channel gating.