Rodent submandibular gland peptide hormones and other biologically active peptides
Introduction
A large body of evidence demonstrates the existence of a cervival sympathetic trunk-submandibular gland (CST-SMG) neuroendocrine axis involved in physiological adjustements maintaining systemic homeostasis in mammals, especially in rodent species [1], [3], [13], [30], [39], [52], [58], [71], [72], [82], [84], [86], [101], [119], [128], [129].
Because rat or mouse submandibular glands (SMGs) have been found to contain and secrete a large number of physiologically active proteins and peptides, such as growth factors, homeostatic proteases, and regulatory peptides, it is not too surprising that these major salivary glands may subserve a range of biologic functions not directly associated with the alimentary digestive system (reviewed in 8, 79). Moreover, as the epithelium of the secretory granular ducts and acinar endpieces in the mouse and rat SMG conforms to the characteristic pattern for protein-secreting cells (e.g. well-developed rough endoplasmic reticulum and numerous stored secretion granules), it is not surprising to find that they store and secrete signaling molecules. In addition, sexual dimorphism is conspicuous in the mandibular glands of some species, particularly in rodents, and this is reflected in the amounts of active peptides present in the two sexes. The most distinguishing aspect is the fact that the rat and mouse SMG is unique in synthesizing and secreting 1) a wide structural and functional variety of polypeptides, for example Renin and NGF; 2) an unexpectedly large amount of certain of these polypeptides in particular in males, where for example, there is approximately 1000 times more NGF in the SMG than in the other producing tissues and 30 to 100 times more NGF in the male than in the female SMG. From the evolutionary point of view, the diversity in types and quantities of secretory proteins produced in SMGs according to species and sex suggests that many different functional adaptations have taken place in response to the needs and demands of the organism.
Data gathered over the past decade provide evidence that rodent SMG possesses endocrine functions. Indeed, as for the classic endocrine axis, the SMG is a source of blood circulating factors involved in peripheral functions. Furthermore, the synthesis and release of these SMG-derived factors are regulated by hormonal and neural mechanisms [2], [10], [11], [17], [20], [39], [65], [81], [127]. As the most striking example, hormones such as androgens, progestins, thyroxine, and adrenergic agents can increase the production of epidermal growth factor (EGF) in the SMG of mice and its level in the circulation. In turn, submandibular gland-derived EGF may play a peripheral role in male reproductive functions by regulating spermatogenesis [128]. Such interrelationships, through systemic hormonal signaling factors, between two integrative organ systems demonstrate the existence of a classic feedback loop connecting both endocrine compartments, i.e. the submandibular and testicular glands. Furthermore, the fact that environmental stress conditions such as aggressive behavior between male mice lead to the systemic secretion of certain SMG peptidic products provides increasing evidence that the SMG factors, as classic endocrine factors, play a role in behavioral and physiological integration, especially reproduction, biochemical homeostasis, and development.
Hence, the submandibular glands of mice and rats appear as a mixed glandular organ with both exocrine and endocrine functions in a way similar to the lower segments of the digestive tract, i.e. stomach, duodenum, and pancreas. However, if SMG is a source of blood-circulating biologically active peptides, most of these peptides also have their well-characterized counterparts in different peripheral organs, where they have a variety of well-known biologial roles. This fact poses the challenging problem of dissecting out the role of some submandibular factor as unique, or major endocrine contributor to homeostatic mechanisms. Besides, SMR1 precursor and its maturation peptides constitute the novel characterized key components of the CST-SMG axis [98], [99]. Moreover SMR1 precursor and its derived peptides, predominantly synthetized and secreted from the rat SMG, in a fashion analogous to that of peptide-hormones of more classic neuroendocrine system, is to date the only SMG-specific component of this axis.
The basic concept of a true endocrine hormone factor implies that it acts on systemic targets, both on tissue cells and circulation plasma proteins to contribute to homeostasis. To do so, they must first enter the conveying bloodstream in response to stimuli of humoral and neural origin. The fact that SMG contain large amounts of the biologically active peptides and secrete them into the saliva does not imply that they are also released into the bloodstream. Consequently, we have restricted this review to well-established SMG-derived peptides that contribute to the plasma levels for their classification as SMG endocrine hormone factors.
Section snippets
Biologically active peptides of rodent SMG as hormonal factors
It is evident that some SMG organic substances, including some polypeptides and steroids, derive from the circulation or from proximate organs, such as neuron projections originating from the autonomic nervous system. For this reason, it is important not only to establish the presence of signaling factors within the SMG, but also to demonstrate their synthesis and secretion by the tissue. Therefore, priority is given in this section to those peptide hormones of well-identified SMG synthesis and
Neuroendocrine control of SMG development and function
In most mammalian species, the SMG are well supplied, on one hand, with both parasympathetic and sympathetic secretomotor nerve fibers, and on the other hand, with blood conveyed from dense capillary networks surrounding the secretory endpieces and the granular ducts. The rodent SMG receives direct postganglionic sympathetic innervation from the superior cervical ganglion, postganglionic parasympathetic innervation from the neurons of the submandibular ganglia, and sensory innervation from the
Conclusion
In summary, there is increasing evidence that rodent SMG, especially the rat and mouse glands, produce a diversity of polypeptides for soluble and membrane bound activities as well as for intracellular and extracellular destinations. By extending its ability to synthesize a diverse array of products, each with the potential to influence both local cells and distal organs of the organism, the SMG has increased its influence on the control of the living system, adapting it to physiological
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