Polarization of calcium signaling and fluid secretion in salivary gland cells

Abstract

The secretion of fluid, electrolytes, and protein by exocrine gland acinar cells is a vectorial process that requires the coordinated regulation of multiple channel and transporter proteins, signaling components, as well as mechanisms involved in vesicular fusion and water transport. Most critical in this is the regulation of cytosolic free [Ca(2+)] ([Ca(2+)](i)) in response to neurotransmitter stimulation. Control of [Ca(2+)](i) increase in specific regions of the cell is the main determinant of fluid and electrolyte secretion in salivary gland acinar cells as it regulates several major ion flux mechanisms as well as the water channel that are required for this process. Polarized [Ca(2+)](i) signals are also essential for protein secretion in pancreatic acinar cells. Thus, the mechanisms that generate and modulate these compartmentalized [Ca(2+)](i) signals are central to the regulation of exocrine secretion. These mechanisms include membrane receptors for neurotransmitters, intracellular Ca(2+) release channels, Ca(2+) entry channels, as well Ca(2+) as pumps and mitochondria. The spatial arrangement of proteins involved in Ca(2+) signaling is of primary significance in the generation of specific compartmentalized [Ca(2+)](i) signals. Within these domains, both local and global [Ca(2+)](i) changes are tightly controlled. Control of secretion is also dependent on the targeting of ion channels and transporters to specific domains in the cell where their regulation by [Ca(2+)](i) signals is facilitated. Together, the polarized localization of Ca(2+) signaling and secretory components drive vectorial secretion of fluid, electrolytes, and proteins in the exocrine salivary glands and pancreas. This review will discuss recent findings which have led to resolution of the molecular components underlying the spatio-temporal control of [Ca(2+)](i) signals in exocrine gland cells and their role in secretion.

Fig. (1). Ca²⁺ signaling mechanisms regulating salivary gland fluid secretion

The figure shows Ca²⁺ mobilizing events in acinar cells that are initiated by a stimulus and lead to fluid secretion. Red arrows indicate mechanisms regulated by [Ca²⁺]_i increase. The coordinated regulation (spatial and temporal) of Ca²⁺ signaling as well as ion channel activation achieves the secretion of fluid from acinar cells.

Fig. (2). Initiation and propagation of cytosolic calcium increases in acinar cells

Release of calcium via apically localized IP₃Rs triggers the initial apical rise in cytosolic [Ca²⁺] following cell stimulation. The calcium signal is then propagated towards the basal region of the cell. It is suggested that apically localized channels are activated first followed by those in the lateral and basal regions of the cell. Activation of calcium entry channels allows a sustained rise in cytosolic [Ca²⁺] which is required to drive fluid secretion.

Fig. (3). Ca²⁺-dependent regulation of cell function

Agonist-stimulated cytosolic calcium changes result from intracellular Ca²⁺ release as well as Ca²⁺ entry. Sustained calcium entry drives several key cellular functions including Ca²⁺-dependent gene expression as well as regulation of ion channel activities. In salivary gland cells, cell lines and acinar cells from mice, TRPC1-mediated Ca²⁺-entry is the primary determinant of sustained K_Ca channel activation. On the other hand, studies in cell lines show that Orai1-mediated Ca²⁺ entry drives NFAT activation, without any contribution of TRPC1. In contrast, NFκB activation requires contributions from both Orai1 and TRPC1.