Salivary secretion in health and disease

Inositol 1,4,5-trisphosphate is a second messenger which regulates intracellular calcium both by mobilizing calcium from internal stores and, perhaps indirectly, by stimulating calcium entry. In these actions it may function with its phosphorylated metabolite, inositol 1,3,4,5-tetrakisphosphate. The subtlety of calcium regulation by inositol phosphates is emphasized by recent studies that have revealed oscillations in calcium concentration which are perhaps part of a frequency-encoded second-messenger system.

Oral homeostasis is dependent upon saliva and its content of proteins. Reflex salivary flow occurs at a low 'resting' rate and for short periods of the day more intense taste or chewing stimuli evoke up to ten fold increases in salivation. The secretion of salivary fluid and proteins is controlled by autonomic nerves. All salivary glands are supplied by cholinergic parasympathetic nerves which release acetylcholine that binds to M3 and (to a lesser extent) M1 muscarinic receptors, evoking the secretion of saliva by acinar cells in the endpieces of the salivary gland ductal tree. Most salivary glands also receive a variable innervation from sympathetic nerves which released noradrenaline from which tends to evoke greater release of stored proteins, mostly from acinar cells but also ductal cells. There is some 'cross-talk' between the calcium and cyclic AMP intracellular pathways coupling autonomic stimulation to secretion and salivary protein secretion is augmented during combined stimulation. Other non-adrenergic, non-cholinergic neuropeptides released from autonomic nerves evoke salivary gland secretion and parasympathetically derived vasointestinal peptide, acting through endothelial cell derived nitric oxide, plays a role in the reflex vasodilatation that accompanies secretion. Neuronal type, calcium-activated, soluble nitric oxide within salivary cells appears to play a role in mediating salivary protein secretion in response to autonomimetics. Fluid secretion by salivary glands involves aquaporin 5 and the extent to which the expression of aquaporin 5 on apical acinar cell membranes is upregulated by cholinomimetics remains uncertain. Extended periods of autonomic denervation, liquid diet feeding (reduced reflex stimulation) or duct ligation cause salivary gland atrophy. The latter two are reversible, demonstrating that glands can regenerate provided that the autonomic innervation remains intact. The mechanisms by which nerves integrate with salivary cells during regeneration or during salivary gland development remain to be elucidated.

The apical (outward-facing) membranes of high-resistance epithelia contain Na+ channels, traditionally identified by their sensitivity to block by the K(+)-sparing diuretic amiloride. Such channels have been characterized in amphibian skin and urinary bladder, renal collecting duct, distal colon, sweat and salivary glands, lung, and taste buds. They mediate the first step of active Na+ reabsorption and play a major role in the maintenance of electrolyte and water homeostasis in all vertebrates. In the past, these channels were classified according to their biophysical and pharmacological properties. The recent cloning of the three homologous channel subunits denoted alpha-, beta-, and gamma-epithelial Na+ channels (ENaC) has provided a molecular definition of at least one class of amiloride-blockable channels. Subsequent studies have established that ENaC is a major Na(+)-conducting pathway in both absorbing and secretory epithelia and is related to one type of channel involved in mechanosensation. This review summarizes the biophysical characteristics, molecular properties, and regulatory mechanisms of epithelial amiloride-blockable Na+ channels. Special emphasis is given to recent studies utilizing cloned ENaC subunits and purified amiloride-binding proteins.