Essential Roles of Calcium Signaling
An essential messenger for intracellular signals, calcium plays diverse and important roles. Among other activities, it regulates biological processes such as nerve signal transmission, muscle contraction, inflammation, vascular permeability and cell death. The storehouse for calcium in a cell is a compartment called the endoplasmic reticulum, or ER. When an outside signal stimulates a cell, the stored calcium is rapidly released from the ER in a pulsatile manner into the cell interior, resulting in activation of a number of key processes affecting synthesis of other signaling molecules, cell growth, differentiation and division. In response to external stress on the cell, release of calcium from these intracellular stores activates CRAC channels, causing even more calcium to move into the cell, and this calcium overload can trigger cell death.
A specific set of calcium-transporting ion channels known as calcium release-activated calcium channels, or CRAC channels, are responsible for replenishing the calcium stores in the ER. The release of calcium from the ER serves as a signal to the Stromal Interaction Molecule 1, or STIM1, protein located on the ER to activate the Orai1 calcium channel on the cell membrane, enabling the influx of calcium.
There is strong genetic evidence linking STIM1 and Orai1 to the way the cell replenishes its calcium stores and to the physiological consequences of disrupting that replenishment. At the cellular level, manipulating STIM1 activity by genetic inactivation or enhancement has been shown to impact calcium transport. Inactivating STIM1 was shown to decrease calcium entry into cells, whereas creating mutations in STIM1 that enhance its activity were shown to increase calcium influx1. At the phenotypic level, people with homozygous genetic mutations in the genes encoding either Orai1 or STIM12 develop the life-threatening condition of severe combined immunodeficiency (SCID). These people lack the ability to mount an effective immune response, so they are at extreme risk of contracting life-threatening infections3. Individuals that are heterozygous for these do not have any notable conditions due to or associated with these genetic deficiencies.
Inhibition of CRAC channels may have therapeutic potential in diseases associated with excessive intracellular calcium levels that drive pathological processes, including acute pancreatitis and acute brain injury.