Regulation of Calcium in Salivary Gland Secretion

Abstract

Neurotransmitter-regulation of fluid secretion in the salivary glands is achieved by a coordinated sequence of intracellular signaling events, including the activation of membrane receptors, generation of the intracellular second messenger, inositol 1,4,5, trisphosphate, internal Ca2l release, and Ca2+ influx. The resulting increase in cytosolic lCa2+l (lCa2+l1) regulates a number of ion transporters, e.g., Ca2+-activated K+ channel, Na+/K+/2ClI co-transporter in the basolateral membrane, and the Ca2l-activated Cl-channel in the luminal membrane, which are intricately involved in fluid secretion. Thus, regulation of lCa2+l1 is central to the regulation of salivary acinar cell function and is achieved by the concerted activities of several ion channels and Ca2+-pumps localized in various cellular membranes. Ca2+ pumps, present in the endoplasmic reticulum and the plasma membrane, serve to remove Ca2+ from the cytosol. Ca2+ channels present in the endoplasmic reticulum and the plasma membrane facilitate rapid influx of Ca2+ into the cytosol from the internal Ca2+ stores and from the external medium, respectively. It is well-established that prolonged fluid secretion is regulated via a sustained elevation in lCa2+l, that is primarily achieved by the influx of Ca2+ into the cell from the external medium. This Ca2`influx occurs via a putative plasma-membranestore-operated Ca2+ channel which has not yet been identified in any non-excitable cell type. Understanding the molecular nature of this Ca2+ influx mechanism is critical to our understanding of Ca2+ signaling in salivary gland cells. This review focuses on the various active and passive Ca2+ transport mechanisms in salivary gland cells-their localization, regulation, and role in neurotransmitter-regulation of fluid secretion. In addition to a historical perspective of Ca2+ signaling, recent findings and challenging problems facing this field are highlighted.

Trp1, a Candidate Protein for the Store-operated Ca2+Influx Mechanism in Salivary Gland Cells

“…6E. Notably, the store-operated Ca 2ϩ influx activity has been suggested to occur via the basolateral membrane of salivary gland and other exocrine gland acinar cells (3,34). Thus, the localization of the Trp1 protein in intact submandibular gland cells is consistent with its proposed physiological function.…”

“…] i regulates the physiological function of a variety of nonexcitable cell types, including salivary gland cells (1)(2)(3). In salivary gland cells, a sustained elevation of [Ca 2ϩ ] i is required for the activation of the ion channels, such as the Ca 2ϩ -activated K ϩ channel and the Ca 2ϩ -activated Cl Ϫ channel, which critically regulate the secretion of fluid and electrolytes.…”

“…[Ca 2ϩ ] i increase in these cells results from intracellular Ca 2ϩ release and from extracellular Ca 2ϩ influx. While release of Ca 2ϩ from the intracellular store(s) triggers a transient increase in [Ca 2ϩ ] i and fluid secretion, sustained fluid secretion is dependent on the influx of Ca 2ϩ from the extracellular medium (3,4). Intracellular Ca 2ϩ release is induced by inositol 1,4,5-trisphosphate (IP 3 ) 1 that is generated in reponse to agonist-dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) (1,5).…”

“…While release of Ca 2ϩ from the intracellular store(s) triggers a transient increase in [Ca 2ϩ ] i and fluid secretion, sustained fluid secretion is dependent on the influx of Ca 2ϩ from the extracellular medium (3,4). Intracellular Ca 2ϩ release is induced by inositol 1,4,5-trisphosphate (IP 3 ) 1 that is generated in reponse to agonist-dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) (1,5). Ca 2ϩ influx across the plasma membrane is mediated via an as yet unknown mechanism referred to as store-operated Ca 2ϩ influx (SOC), or capacitative calcium entry, that is activated by the depletion of Ca 2ϩ from the internal Ca 2ϩ store (3, 6 -8).…”

Inhibitory effects of autoantibodies on the muscarinic receptors in Sjögren's syndrome

“…2 The mechanisms of the salivary secretion are well documented. [3][4][5][6] Stimulus-secretion coupling in salivary gland acinar cells is initiated by the release of acetylcholine (ACh) from the parasympathetic nerves, which is mediated by an increase in the intracellular Ca 2 þ level, [7][8][9] which culminates in the activation of the Ca 2 þ -dependent K þ and Cl À channels. A disturbance in any step of these signal transduction processes will result in the decrease of fluid secretion.…”