Selective processing of submandibular rat 1 protein at dibasic cleavage sites

Abstract

The amino acid sequence of submandibular rat 1 (SMR1) protein, deduced from its cDNA sequence, led to the prediction that the SMR1 gene encodes a hormone‐like precursor [Rosinski‐Chupin, I., Tronik, D. & Rougeon, F. (1988) Proc. Natl Acad. Sci. USA 85, 8553–8557]. SMR1 contains an N‐terminal putative secretory signal sequence and a tetrapeptide (QHNP), located between dibasic amino acids which constitute the most common signal for prohormone processing. We have isolated and characterized from the male rat submandibular gland and its secretions three structurally related peptides, namely an undecapeptide (VRGPRRQHNPR), a hexapeptide (RQHNPR) and a pentapeptide (QHNPR) generated from SMR1 by selective proteolytic cleavages at pairs of arginine residues. The biosynthesis of these peptides is subjected to distinct regulatory pathways depending on the organ, sex and age of the rat. Furthermore, the peptides are differentially distributed in the submandibular gland and in resting or epinephrine‐elicited submandibular salivary secretions, suggesting distinct proteolytic pathways for their maturation. The undecapeptide is generated in the gland of both male and female rats, but under basal conditions it is only released into the saliva in male animals. The hexapeptide is produced in large amounts in the gland of adult male rats and released into the saliva in both resting and stimulated conditions. The pentapeptide appears only in the male saliva and is present mostly under stimulated conditions. In addition, administration of epinephrine induces the release of the hexapeptide from the submandibular gland into the bloodstream. The evidence indicates that the rat submandibular gland can function as a dual exocrine and endocrine organ for the SMR1‐derived hexapeptide, as has been reported for nerve growth factor, epidermal growth factor, renin and kallikrein. Although the biological activities of the SMR1‐derived peptides are not yet known, their high production and adrenergic‐induced release only into the saliva and bloodstream of adult male rats, suggest a physiological involvement in some male‐specific processes.

Human Opiorphin, a natural antinociceptive modulator of opioid-dependent pathways

“…Rat sialorphin is an endocrine peptide signal whose expression is activated by androgen regulation and whose secretion is stimulated under adrenergic-mediated response to environmental stress in male rats. It is a physiological inhibitor of the membrane-anchored rat NEP activity and is a powerful inhibitor of pain sensation in rats (9)(10)(11)(12)(13). To our knowledge, bovine spinorphin and rat sialorphin are the only identified natural enkephalin catabolism inhibitors inducing antinociception in mammals (8,13).…”

Sialorphin, a natural inhibitor of rat membrane-bound neutral endopeptidase that displays analgesic activity

“…In common with other peptide hormones, the three peptides are selectively matured from the precursor in vivo by cleavage at multibasic sites by a paired basic amino acid-converting enzyme (probably furin). They are differentially accumulated in the submandibular gland, in an age-dependent and sex-related manner, and are released both locally and systemically in response to neuroendocrine stimuli (8).…”

Acinar Cells Are Target Cells for Androgens in Mouse Submandibular Glands

“…The first gene of this family to be described was the rat VCSA1 gene, which is expressed mainly in SMG and encodes the SMR1 protein (Rosinski-Chupin et al 1988). SMR1 is a prohormone protein, whose maturation generates three related peptides, which are released into the saliva and bloodstream (Rougeot et al 1994). The target organs for the final maturation product, a pentapeptide, were recently shown to be primarily kidney and the bone, suggesting that this peptide might be involved in the modulation of mineral balance (Rougeot et al 1997).…”