51110-01-1

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Questions And Answer

• Discovery

  This is a tetradecapeptide exerting a growth hormone (GH) release-inhibiting activity. SS also has a large variety of neuromodulatory and gastrointestinal actions, mostly as an inhibitory hormone. SS of 14 aa residues (SS-14) was first isolated from ovine hypothalamic extracts by Roger Guillemin’s group in 1973 and was originally named GH inhibiting factor. An N-terminally extended form of 28 aa residues (SS-28) was isolated later from the porcine gut. SS cDNA that encodes a precursor for SS-14 and SS-28, a product of the SS1 gene (approved symbol SST), was first cloned from the anglerfish pancreas in 1980. In this report, another SS cDNA encoding a different precursor (formerly called SSII), a product of the SS3 gene, was also isolated. Subsequently, cDNAs and genes encoding SS precursors have been identified in many animals by molecular cloning and bioinformatic analyses, and so far six paralogous genes (SS1, SS2, SS3, SS4, SS5, and SS6) have been identified in vertebrates. Accordingly, two SS-related peptides, cortistatin (CST)5 and neuronostatin, have been identified.;

• Structure

  SS-14 and SS-28 contain a disulfide bridge and have a cyclic structure. CST, a product of the SS2/CST gene, is 14–17 aa residues in length, depending on the species, and contains the SS2 signature, a proline residue at position 2. CST in placental mammals exhibits an additional lysine residue at its C-terminal extremity. Neuronostatin is a 13-residue amidated peptide that is flanked with the signal peptide of the SS1 precursor, and is an acyclic peptide.  The aa sequence of SS-14 is fully conserved in vertebrates. SS-28 in mammals that contains the SS-14 moiety at its C-terminal shares 40%–66% sequence identity with its counterparts in fish. Mr 1638 (SS-14), 3149 (SS-28). Soluble in water, acid, and methanol. Stable in solution at -80°C for more than a year. Plasma half-life is <3min.
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• Gene, mRNA, and precursor

  The human preproSS gene (SS1), SST, location 3q28, consists of two exons. Mammalian SS-14 and SS-28 are derived from preproSS1 of 116 aa residues by specific proprotein convertases (PCs) through tissue-specific posttranslational processing. In vertebrates, six SS genes have been identified, and all these paralogs are present in teleost fish while only SS1 and SS2/CST are present in tetrapods. Phylogenetic and comparative genomic analyses showed that whole-genome duplications, local duplications, and gene losses contribute to the divergent evolution of SS genes.;

• Clinical implications

  Somatostatinoma is a malignant tumor that arises from transformed D cells in the pancreatic islets or duodenum. Somatostatinomas are associated with malabsorption, diabetes mellitus, steatorrhea, and cholelithiasis. In gastroenteropancreatic tumors, high levels of SS receptor expression have been found, and specifically designed analogs are used for tumor imaging and radiotherapy. SS deficiency causes persistent Helicobacter pylori infection in the patient with chronic gastritis.;

• Receptors

  SS receptors belong to the family of seventransmembrane-domain GPCRs. There are five subtypes (sst1–sst5), and all these receptors bind to SS and CST with high affinity.7 The structural and functional characteristics of these receptors in humans, including signal transduction pathways, agonists, and antagonists.
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• Biological functions

  In the anterior pituitary, SS inhibits the release of GH and thyroid-stimulating hormone (TSH). Pulsatile GH secretion reflects the pulsatile release of both SS and GHRH in a reciprocal fashion. In fish, SS-14 inhibits the release of GH, prolactin, and insulin. In the brain, SS has a variety of neuromodulatory roles in learning, cognitive functions, locomotor activity, anxiety, and depression. CST has physiological functions, such as depression of neuronal activity and induction of slowwave sleep. Moreover, SS exerts inhibitory effects on various gastrointestinal functions, including gastric acid secretion, gastric emptying, intestinal motility, and release of insulin, glucagon, and various gastrointestinal hormones.;

• Regulation of synthesis and release

  SS secretion in the gastrointestinal tract is regulated by the autonomous nervous system and various gut regulatory peptides including gastrin, cholecystokinin (CCK), and substance P. The synthesis and release of hypothalamic SS are regulated by GH, growth hormone-releasing hormone (GHRH), and glucose.;

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