Elsevier

Peptides

Volume 21, Issue 3, March 2000, Pages 443-455
Peptides

Rodent submandibular gland peptide hormones and other biologically active peptides

https://doi.org/10.1016/S0196-9781(00)00158-3Get rights and content

Abstract

The cervical sympathetic trunk-submandibular gland neuroendocrine axis plays an integral role in physiological adaptations and contributes to the maintenance of systemic homeostasis, particularly under the ‘stress conditions’ seen with tissue damage, inflammation, and aggressive behavior. The variety of polypeptides, whose release from acinar and ductal cells is under sympathetic nervous system control, offers coordinated and progressive levels of endocrine communication. Proteolytic enzymes (e.g. the kallikreins and furin maturases) are involved in the conversion of inactive precursors (e.g. Pro-EGF and SMR1) into biologically active molecules (e.g. EGF, SMR1-pentapeptide), which act on local or distant targets and thereby modulate the homeostatic process.

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

References (138)

  • O. Happola et al.

    Peptide YY-like immunoreactivity in sympathetic neurons of the rat

    Neuroscience

    (1990)
  • A.D. Hershey et al.

    Organization, structure, and expression of the gene encoding the rat substance P receptor

    J Biol Chem

    (1991)
  • M.G. Humphreys–Beher

    Elimination of isoproterenol-induced proline-rich protein biosynthesis in rat salivary glands after adult thyroidectomy

    Biochem Pharmacol

    (1987)
  • Y. Iwabuchi et al.

    Effects of vasoactive intestinal peptide and its homologous on the acetylcholine mediated secretion of fluid and protein from the rat submandibular gland

    Gen Pharmacol

    (1995)
  • Y. Iwabuchi et al.

    Effects of calcitonin and calcitonin gene-related peptide on the substance P-mediated secretion of fluid from the rat submandibular gland

    Gen Pharmacol

    (1998)
  • M. Jankowski et al.

    Natriuretic peptide system in the rat submaxillary gland

    Regul Pept

    (1996)
  • M. Kerr et al.

    Detection of insulin and insulin-like growth factors I and II in saliva and potential synthesis in the salivary glands of mice. Effects of type I diabetes mellitus

    Biochem Pharmacol

    (1995)
  • L. Klimaschewski et al.

    Target-dependent plasticity of galanin and vasoactive intestinal peptide in the rat superior cervical ganglion after nerve lesion and re-innervation

    Neuroscience

    (1996)
  • Z. Krozowski et al.

    Type I corticosteroid receptor-like immunoreactivity in the rat salivary glands and distal colonmodulation by corticosteroids

    Mol Cell Endocrinol

    (1992)
  • S. Lahtivirta et al.

    Effect of sialectomy on the superior cervical ganglion sympathetic neurons in young adult and aged mice

    Mech Ageing Dev

    (1992)
  • A. Laniyonu et al.

    Different tachykinin receptor subtypes are coupled to the phosphoinositide or cyclic AMP signal transduction pathways in rat submandibular cells

    FEBS Lett

    (1988)
  • A. Laniyonu et al.

    Muscarinic M3 receptors are coupled to two signal transduction pathways in rat submandibular cells

    Eur J Pharmacol

    (1990)
  • R. Mathison et al.

    Neuroendocrine regulation of inflammation and tissues repair by submandibular gland factors

    Immunol Today

    (1994)
  • R. Mathison et al.

    Attenuation of intestinal and cardiovascular anaphylaxis by the salivary gland tripeptide FEG and its D-isomeric analog feG

    Peptides

    (1998)
  • H. Matsumoto et al.

    Abundance of endothelin-3 in rat intestine, pituitary gland and brain

    Biochem Biophys Res Commun

    (1989)
  • M. Mogi et al.

    Differential expression of transforming growth factor-α and epidermal growth factor during postnatal development of rat submandibular gland

    Biochem Biophys Res Commun

    (1995)
  • T. Moreau et al.

    Protein products of the rat kallikrein family

    J Biol Chem

    (1992)
  • T. Okamoto et al.

    Androgen-dependent expression of fibroblast growth factor-1 in submaxillary gland of mouse

    Biochem Biophys Res Com

    (1996)
  • E. Alleva et al.

    An updated role for nerve growth factor in neurobehavioural regulation of adult vertebrates

    Rev Neurosci

    (1993)
  • L. Aloe et al.

    Aggressive behavior induces release of nerve growth factor from mouse salivary gland into the bloodstream

    Proc Natl Acad Sci USA

    (1986)
  • O. Amano et al.

    Expression and localization of hepatocyte growth factor in rat submandibular gland

    Growth Factors

    (1994)
  • T. Antakly et al.

    Cell-specific expression of the glucocorticoid receptor within granular convoluted tubules of the rat submaxillary gland

    Endocrinology

    (1991)
  • P.L. Ashley et al.

    Kallikrein-related mRNAs of the rat submaxillary glandnucleotide sequences of four distinct types including tonin

    Biochemistry

    (1985)
  • T. Barka

    Biologically active polypeptides in submandibular glands

    J Histochem Cytochem

    (1980)
  • T. Barka et al.

    Stimulation of secretion of epidermal growth factor and amylase by cyclocytidine

    Cell Tissue Res

    (1978)
  • T. Berg et al.

    Enzymatic activity of rat submandibular gland kallikrein released into blood

    Am J Physiol

    (1985)
  • T. Berg et al.

    Exocrine and endocrine release of kallikrein after reflex-induced salivary secretion

    Acta Physiol Scand

    (1990)
  • J. Bing et al.

    Cause of the continuous rise in plasma renin concentration after removal of manipulated submaxillary glands in nephrectomized mice

    Acta Path Microbiol Scand

    (1977)
  • J. Bing et al.

    Renin in the submaxillary gland

    J Histochem Cytochem

    (1980)
  • J. Bing et al.

    Differences in renal and submaxillary renin release after stimulation with isoprenaline and noradrenaline

    Acta Physiol Scand

    (1979)
  • J. Bing et al.

    In mice aggressive behavior provokes vast increase in plasma renin concentration, causing only slight, if any, increase in blood pressure

    Acta Physiol Scand

    (1979)
  • R. Boucher et al.

    Tonin, angiotensin II system. A review

    Circ Res

    (1977)
  • R.I. Byyny et al.

    Epidermal growth factoreffects of androgens and adrenergic agents

    Endocrinology

    (1974)
  • P.S. Campbell et al.

    Differential distribution of an estrogen receptor in the submandibular and parotid salivary glands of female rats

    Endocr Res

    (1990)
  • S. Cohen et al.

    Human epidermal growth factorisolation and chemical and biological properties

    Proc Natl Acad Sci USA

    (1975)
  • D.I. Cook et al.

    Secretion by the major salivary glands

  • J.P. Dehaye et al.

    Beta-adrenergic stimulation and cAMP mobilize Ca2+ from an IP3-insensitive pool in rat submandibular granular ducts

    Am J Physiol

    (1993)
  • D. Deville de Pieriere et al.

    Age-dependent changes in insulin-like immunoreactivity in rat submandibular salivary glands

    Eur J Oral Sci

    (1996)
  • D. Deville de Pieriere et al.

    Vanadyl treatment normalizes submandibular salivary gland in insulin-like immunoreactivity in streptozotocin-diabetic rats

    Horm Metab Res

    (1998)
  • C. Dolce et al.

    Effects of sialoadenectomy and exogenous EGF on molar drift and orthodontic tooth movement in rats

    Am J Physiol

    (1994)
  • Cited by (42)

    • A novel approach to describing the pancreas and submandibular gland: Can they be classified as primary and secondary tissue organs?

      2022, Acta Histochemica
      Citation Excerpt :

      Rodents’ SMG secretions into the blood have been discovered for glucagon (Lawrence et al., 1977), renin (Pedersen and Poulsen, 1982), and sialorphin (Rougeot et al., 1994, 1998, 1997). These peptides can affect growth and differentiation, enzymatic function, homeostatic maintenance, and adaptation to stress (Barka, 1980; Mori et al., 1992; Rougeot et al., 2000). In addition to sharing may similar characteristics, the pancreas and SMGs interact with one another on a hormonal level via growth factors.

    • Copious urinary excretion of a male Syrian hamster (Mesocricetus auratus) salivary gland protein after its endocrine-like release upon β-adrenergic stimulation

      2013, General and Comparative Endocrinology
      Citation Excerpt :

      This possibility, as well as the possibility that above treatments might concomitantly release MSP into circulation, needs investigation by SDS–PAGE and/or Western-blot of saliva and urine of treated hamsters. Moreover, aggressive behavior in mice is reported to induce release of specific proteins from SMG ductal cells into blood and saliva (Nexø et al., 1981; Rougeot et al., 2000). During stress (aggression-induced or otherwise) increased release of noradrenaline (at sympathetic nerve endings in salivary gland) and adrenaline (into blood, from adrenals) can result in adrenergic stimulation of SMG mediated via α- and β-adrenoceptors (Nater and Rohleder, 2009; Proctor and Carpenter, 2007).

    • Tickling stimulation causes the up-regulation of the kallikrein family in the submandibular gland of the rat

      2013, Behavioural Brain Research
      Citation Excerpt :

      Klk1 (true tissue kallikrein) is involved in the processing of kininogens in kinins, such as bradykinin, which is a potent mediator of functional vasodilatation, whereas Klk2 (Klk1c2, Tonin) can release angiotensin II, the most powerful vasoconstrictor, directly from angiotensinogen. The other Klk-related peptidases, which exhibit different substrate specificity and different susceptibility to the inhibitors from each other and from those of Klk1 [28], could be involved in the processing of peptides other than kinins and angiotensins. Tissue Klk has been shown in vitro to process various peptide precursors including low density lipoprotein, atrial naturiuretic factor, prorenin, proinsulin, vasoactive intestinal peptide and procollagenase [26,27].

    View all citing articles on Scopus
    View full text