Somatostatin

Somatostatin (sometimes known as somatotropin release-inhibiting factor; SRIF) is a peptide hormone comprising two peptides, of 14 and 28 amino acids, referred to as SS-14 and SS-28, respectively. Both forms of somatostatin are generated by proteolytic cleavage of prosomatostatin, which itself is derived from preprosomatostatin. Like all peptide hormones, somatostatin is packaged in large dense core secretory vesicles ahich are secreted by calcium-dependent exocytosis. Somatostatin is secreted by neurosecretory neurons of the hypothalamus, and also by delta cells of stomach, intestine, and pancreas. It acts via specific, high affinity G-protein coupled receptors. The relative amounts of SS-14 andSS-28 secreted depends upon the tissue; SS-14 is the predominant form produced in the brain and apparently the only form secreted from the pancreas, whereas the intestine secretes mostly SS-28. The two forms can have different biological potencies. SS-28 is about ten times as potent as SS-14 in inhibiting growth hormone secretion, but is less potent in inhibiting glucagon secretion. Five subtypes of stomatostatin receptors have been identified, which activate distinct intracellelar signalling mechanisms, although all inhibit adenylyl cyclase. Four of the five receptors do not differentiate between SS-14 and SS-28.

Sequence

The preprosomatostatin coding region of the human somatostatin I gene predicts a 116-amino acid precursor protein contains somatostatin-14 and -28 at its COOH terminus. The predicted amino acid sequence of human SS-28 is identical to that of SS-28 from porcine and ovine species.

SS-14; molecular weight 1627.9

AGCKNFFWKTFTSC (Disulfide bridge: 3-14)

H - Ala - Gly - Cys - Lys - Asn - Phe - Phe - Trp - Lys - Thr - Phe - Thr - Ser - Cys - OH (Disulfide bridge: 3 - 14)

SS-28; molecular weight 3148.6

SANSNPAMAPRERKAGCKNFFWKTFTSC (Disulfide bridge: 17-28)

H - Ser - Ala - Asn - Ser - Asn - Pro - Ala - Met - Ala - Pro - Arg - Glu - Arg - Lys - Ala - Gly - Cys - Lys - Asn - Phe - Phe - Trp - Lys - Thr - Phe - Thr - Ser - Cys - OH (Disulfide bridge: 17 - 28)

Receptors

There are five known somatostatin receptors, SSTR1 - SSTR5.

Actions

Somatostatin acts by both endocrine and paracrine pathways. Most of the somatostatin in the circulation comes from the pancreas and gastrointestinal tract.

Somatostatin inhibits the secretion of many other hormones; in particular, somatostatin released from the hypothalamus inhibits the release of growth hormone (GH) and thyroid-stimulating hormone (TSH) from the anterior pituitary gland. Cells within pancreatic islets secrete insulin, glucagon and somatostatin, and there, somatostatin acts primarily in a paracrine manner to inhibit the secretion of both insulin and glucagon. It also suppresses pancreatic exocrine secretions, by inhibiting cholecystokinin-stimulated enzyme secretion and secretin-stimulated bicarbonate secretion. Somatostatin is also secreted by cells in the gastro-intestinal epithelium, and by neurons in the enteric nervous system, and this secretion inhibits secretion of many other gastro-intestinal hormones, including gastrin, cholecystokinin, secretin and vasoactive intestinal peptide. Somatostatin also suppresses secretion of gastric acid and pepsin, lowers the rate of gastric emptying, and reduces smooth muscle contractions and blood flow in the intestine. These actions slow the rate of nutrient absorption.

Synthetic substitutes

Octreotide (brand name, Sandostatin® and Sandostatin LAR® Depot.; Novartis Pharmaceuticals]]) is a synthetic substitute of somatostatin which mimics natural somatostatin pharmacologically, but is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. The FDA has approved the use of a form of this peptide octreotide acetate, for the treating acromegaly, and for treating diarrhea and flushing episodes associated with carcinoid syndrome, and treatment of diarrhea in patients with vasoactive intestinal peptide-secreting tumors. Octreotide has also been used off-label for treating severe, refractory diarrhea from other causes. It is also used for treating prolonged recurrent hypoglycemia after sulfonylurea overdose. Somatostatin and its synthetic analogs are used clinically to treat a variety of neoplasms (tumors). It is also used for the treatment of giantism (caused by congentital excess secretion of growth hormone) and acromegaly (exces grpwth hormone secretion that occurs in middle-aged men and women).

Somatostatin in the brain

Somatostatin is produced by neuroendocrine neurons of the periventricular nucleus of the hypothalamus. These neurons project to the median eminence, where somatostatin is released from neurosecretory nerve endings into the hypothalamo-hypophysial portal circulation. These blood vessels carry somatostatin to the anterior pituitary gland, where somatostatin inhibits the secretion of growth hormone from somatotrope cells. The somatostatin neurons in the periventricular nucleus mediate negative feedback effects of growth hormone on its own release; the somatostatin neurons respond to high circulating concentrations of growth hormone and somatomedins by increasing the release of somatostatin, so reducing the rate of secretion of growth hormone.

Somatostatin is also produced by several other neuronal populations that project centrally - i.e. to other areas of the brain, and somatostatin receptors are expressed at many different sites in the brain. In particular, there ae populations of somatostatin neurons in the arcuate nucleus, the hippocampus and the brainstem nucleus of the solitary tract.