Calcium signalling in salivary gland physiology and dysfunction

Studies over the past four decades have established that Ca2+ is a critical factor in control of salivary gland function and have led to identification of the critical components of this process. The major ion transport mechanisms and ion channels that are involved in fluid secretion have also been established. The key event in activation of fluid secretion is an increase in [Ca2+]i triggered by inositol 1,4,5‐trisphosphate (IP3)‐induced release of Ca2+ from ER via the IP3 receptor (IP3R). IP3Rs determine the site of initiation and the pattern of the [Ca2+]i signal in the cell. However, Ca2+ entry into the cell is required to sustain the elevation of [Ca2+]i and fluid secretion and is mediated by the store‐operated Ca2+ entry (SOCE) mechanism. Orai1, TRPC1, TRPC3 and STIM1 have been identified as critical components of SOCE in these cells. Cells finely tune the generation and amplification of [Ca2+]i signals for regulation of cell function. An important emerging area is the concept that unregulated [Ca2+]i signals in cells can directly cause cell damage, dysfunction and disease. Alternatively, aberrant [Ca2+]i signals can also amplify and increase the rates of cell damage. Such defects in Ca2+ signalling have been described in salivary glands in conjunction with radiation‐induced loss of salivary gland function as well as in the salivary defects associated with the autoimmune exocrinopathy Sjögren's syndrome. Such defects have been associated with altered function or expression of key Ca2+ signalling components, such as STIM proteins and TRP channels. These studies offer new avenues for examining the mechanisms underlying the disease and development of novel clinical targets and therapeutic strategies. Ca2+ signalling in cells is a double‐edged sword: the tool kit that is involved in maintaining and regulating normal cell function can also be involved in pathophysiology. Normal physiological stimuli induce cytosolic Ca2+ signals by regulating the Ca2+ signalling toolkit, which includes various Ca2+ flux pathways as well as Ca2+‐regulated targets such as ion channels, enzymes and transcription factors. Under these conditions, Ca2+ homeostasis is maintained and cells display physiological responses. However, pathophysiological stimuli often generate unregulated and aberrant Ca2+ signals in cells due to modification of the same toolkit. This results in loss of Ca2+ homeostasis that can either cause or amplify the disease process.