Calcium signalling in salivary gland physiology and dysfunction

Abstract

Studies over the past four decades have established that Ca(2+) 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 [Ca(2+) ]i triggered by inositol 1,4,5-trisphosphate (IP3 )-induced release of Ca(2+) from ER via the IP3 receptor (IP3 R). IP3 Rs determine the site of initiation and the pattern of the [Ca(2+) ]i signal in the cell. However, Ca(2+) entry into the cell is required to sustain the elevation of [Ca(2+) ]i and fluid secretion and is mediated by the store-operated Ca(2+) 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 [Ca(2+) ]i signals for regulation of cell function. An important emerging area is the concept that unregulated [Ca(2+) ]i signals in cells can directly cause cell damage, dysfunction and disease. Alternatively, aberrant [Ca(2+) ]i signals can also amplify and increase the rates of cell damage. Such defects in Ca(2+) 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 Ca(2+) 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.

Figure 1. Schematic representation of Ca²⁺‐dependent regulation of fluid secretion in salivary gland acinar cells

Key molecular components involved in initiation and generation of [Ca²⁺]_i signals are indicated in the figure, as are ion channels and transporters regulated by [Ca²⁺]_i elevation.

Figure 2. Ca²⁺ signalling in salivary gland dysfunction

Two conditions, IR and Sjögren's syndrome, induce salivary gland dysfunction that leads to xerostomia. TRPM2 has been identified as a target for IR‐generated ROS in cells, and loss of TRPM2 function protects against IR‐induced defect in salivary gland acinar cell function. IR‐induced salivary gland dysfunction can include as yet unconfirmed effects on mitochondria and DNA (dashed arrows). Sjögren's syndrome also results in loss of salivary fluid secretion and xerostomia. While the condition causes inflammation in the gland, the intracellular mediators of the disease are not known. Decreases in IP₃R function, cytokine generation and changes in gene expression could contribute to initiation and the progress of the disease.