Regulation of salivary gland function by autonomic nerves

Abstract

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.

Introduction

Saliva in the mouth is the mixed product of 3 pairs of major salivary glands, the parotid, submandibular and sublingual glands as well as numerous ‘minor’ salivary glands found in the submucosa under most soft tissue surfaces in the mouth. Whole mouth saliva also contains small amounts of other fluids and products of the mucosal surface. Like other mucosal fluids saliva forms a mobile layer on the mucosal surface and contains an array of components that fulfil important functions. In fact protection of the oral mucosal surface is provided by components which are also present in other mucosal fluids, such as mucins (MUC5B and MUC7) and secretory IgA (sIgA) as well as components which appear to be less widely detected on other surfaces or may be peculiar to saliva (e.g. histatins, agglutinin). Unlike other mucosal fluids saliva contains a range of components that interact with and protect teeth (e.g. proline rich proteins, statherins). Saliva is crucial in maintaining the integrity of the oral mucosal surface and in preserving an ecological balance (Hay and Bowen, 1999). The roles played by different salivary components in protecting the soft and hard tissues of the mouth has been reviewed by others (Amerongen and Veerman, 2002).

Most of the components of saliva in the mouth – water, ions, proteins – are actively secreted by salivary glands. The secretory endpiece of salivary glands consists of acinar secretory units made up of acinar cells which are responsible for synthesising and secreting most of the functionally important protein components of saliva (Segawa and Yamashina, 1998, Proctor, 1998). The acini are specialised to each gland and are classified to reflect the proteins secreted by each type of acini—the parotid glands have mainly serous, the sublingual mainly mucous and the submandibular a mixture of the two. In the same way that diets vary from one species to another so too are the salivary glands which are specialised for the diet (Tandler and Phillips, 1998) and therefore this simple classification of acinar cells does not fit all species. Water and electrolytes are actively transported by acinar cells and then the electrolyte content of saliva is modified, principally with the removal of sodium chloride during passage through the ductal system to the mouth (Melvin et al., 2005, Turner and Sugiya, 2002). Saliva is therefore converted from an isotonic to a hypotonic solution—which aids the detection of salt in the diet. This is an energy rich process so that the most active ducts have large numbers of mitochondria located in the basolateral part of the cells leading to their description as striated ducts. In addition to removing ions they also add potassium and bicarbonate—the latter forms an important component of the buffering system of saliva that prevents dissolution of teeth by acid producing bacteria. Most ductal cells secrete only small amounts of protein. However, granular ductal cells, which are peculiar to submandibular glands of some rodents including mouse and rat, are packed full of tissue kallikreins. In addition to the parenchymal component of salivary glands there are myoepithelial cells (see Fig. 1) which support the acini in some but not all salivary glands and may help expel secretions from the ductal system. Plasma cells present in the gland interstitium, secrete immunoglobulins which are transported by salivary cells into saliva and a dense network of blood vessels supply the fluid component of saliva (via the interstitial space). Controlling and influencing all these cells are parasympathetic and sympathetic autonomic nerves which work together harmoniously to evoke secretion.