Ca²⁺ signaling and regulation of fluid secretion in salivary gland acinar cells

Abstract

Neurotransmitter stimulation of plasma membrane receptors stimulates salivary gland fluid secretion via a complex process that is determined by coordinated temporal and spatial regulation of several Ca(2+) signaling processes as well as ion flux systems. Studies over the past four decades have demonstrated that Ca(2+) is a critical factor in the control of salivary gland function. Importantly, critical components of this process have now been identified, including plasma membrane receptors, calcium channels, and regulatory proteins. The key event in activation of fluid secretion is an increase in intracellular [Ca(2+)] ([Ca(2+)]i) triggered by IP3-induced release of Ca(2+) from ER via the IP3R. This increase regulates the ion fluxes required to drive vectorial fluid secretion. IP3Rs determine the site of initiation and the pattern of [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. This Ca(2+) influx pathway, store-operated calcium influx pathway (SOCE), has been studied in great detail and the regulatory mechanisms as well as key molecular components have now been identified. Orai1, TRPC1, and STIM1 are critical components of SOCE and among these, Ca(2+) entry via TRPC1 is a major determinant of fluid secretion. The receptor-evoked Ca(2+) signal in salivary gland acinar cells is unique in that it starts at the apical pole and then rapidly increases across the cell. The basis for the polarized Ca(2+) signal can be ascribed to the polarized arrangement of the Ca(2+) channels, transporters, and signaling proteins. Distinct localization of these proteins in the cell suggests compartmentalization of Ca(2+) signals during regulation of fluid secretion. This chapter will discuss new concepts and findings regarding the polarization and control of Ca(2+) signals in the regulation of fluid secretion.

Keywords: Calcium signaling; IP3R; Orai1; STIM1; Salivary fluid secretion; TRPC1.

Figure 1. Ca²⁺ signaling and regulation of fluid secretion in salivary gland acinar cells

This figure illustrates the key signaling events and components involved in regulation of vectorial fluid secretion in salivary acinar cells. Increase in cytosolic calcium as a consequence of neurotransmitter stimulation, intracellular Ca²⁺ release and Ca²⁺ entry, leads to regulation of ion transport, generation of an osmotic gradient, and water flow via the apical membrane of the cell.

Figure 2. Spatiotemporal regulation of Ca²⁺ signals in salivary gland acinar cells

Left: images show Ca²⁺ changes in an acinar cell following stimulation. The first increase is detected in the acinar region which then spreads to the basal region, although apical [Ca²⁺] is relatively higher. Right: The illustration depicts the underlying Ca²⁺ fluxes that determine [Ca²⁺]_i changes in the cell. The initial increase occurs by release of Ca²⁺ via the IP₃R at the apical pole. Ca²⁺ entry channels Orai1 and TRPC1 contribute to the global spread of Ca²⁺ in the cell, with TRPC1 being the primary component of this increase. While the apical membrane in acinar cells in the illustration is presented in a simplified manner, it is likely to be highly invaginated and thus could extend within the cell to areas close to or even past the tight junction region. Such an arrangement would bring apical components relatively close to the ion channels in the lateral region and facilitate Ca²⁺ sensing by the latter. Further studies will be required to establish this.

Figure 3. Regulation of TRPC1 and Orai1 in cellular microdomains

The figure illustrates regulation of the calcium entry channels in various cellular domains. Release of intracellular Ca²⁺ in the apical region via IP₃R activates STIM1 which translocates towards the plasma membrane binds to Orai1 and activates it. Ca²⁺ entry via Orai1 recruits TRPC1 to the membrane where it is also activated by STIM1. Further rise in [Ca²⁺]_i along the basolateral region by the activites of the IP₃R and RyR could drive recruitment of additional TRPC1 in these regions of the cell and generate sustained increases in [Ca²⁺]_i. This latter trafficking of TRPC1, i.e. Ca²⁺ dependent but Orai1 independent, has yet to be experimentally validated.