Structural and stoichiometric determinants of Ca2 + release-activated Ca2 + (CRAC) channel Ca2 +-dependent inactivation

Abstract

Depletion of intracellular Ca2+ stores in mammalian cells results in Ca2+ entry across the plasma membrane mediated primarily by Ca2+ release-activated Ca2+ (CRAC) channels. Ca2+ influx through these channels is required for the maintenance of homeostasis and Ca2+ signaling in most cell types. One of the main features of native CRAC channels is fast Ca2+-dependent inactivation (FCDI), where Ca2+ entering through the channel binds to a site near its intracellular mouth and causes a conformational change, closing the channel and limiting further Ca2+ entry. Early studies suggested that FCDI of CRAC channels was mediated by calmodulin. However, since the discovery of STIM1 and Orai1 proteins as the basic molecular components of the CRAC channel, it has become apparent that FCDI is a more complex phenomenon. Data obtained using heterologous overexpression of STIM1 and Orai1 suggest that, in addition to calmodulin, several cytoplasmic domains of STIM1 and Orai1 and the selectivity filter within the channel pore are required for FCDI. The stoichiometry of STIM1 binding to Orai1 also has emerged as an important determinant of FCDI. Consequently, STIM1 protein expression levels have the potential to be an endogenous regulator of CRAC channel Ca2+ influx. This review discusses the current understanding of the molecular mechanisms governing the FCDI of CRAC channels, including an evaluation of further experiments that may delineate whether STIM1 and/or Orai1 protein expression is endogenously regulated to modulate CRAC channel function, or may be dysregulated in some pathophysiological states.