Somatostatin has two active forms produced by the alternative cleavage of a single preproprotein: one consisting of 14 amino acids (shown in infobox to right), the other consisting of 28 amino acids.[7][8]
Among the vertebrates, there exist six different somatostatin genes that have been named SS1, SS2, SS3, SS4, SS5 and SS6.[9]Zebrafish have all six.[9] The six different genes, along with the five different somatostatin receptors, allow somatostatin to possess a large range of functions.[10]
Humans have only one somatostatin gene, SST.[11][12][13]
Somatostatin released in the pyloric antrum travels via the portal venous system to the heart, then enters the systemic circulation to reach the locations where it will exert its inhibitory effects. In addition, somatostatin release from delta cells can act in a paracrine manner.[14]
In the stomach, somatostatin acts directly on the acid-producing parietal cells via a G-protein coupled receptor (which inhibits adenylate cyclase, thus effectively antagonising the stimulatory effect of histamine) to reduce acid secretion.[14] Somatostatin can also indirectly decrease stomach acid production by preventing the release of other hormones, including gastrin and histamine which effectively slows down the digestive process.[citation needed]
Brain
Sst is expressed in interneurons in the telencephalon of the embryonic day 15.5 mouse. Allen Brain Atlases
Somatostatin is produced by neuroendocrine neurons of the ventromedial nucleus of the hypothalamus. These neurons project to the median eminence, where somatostatin is released from neurosecretory nerve endings into the hypothalamohypophysial system through neuron axons. Somatostatin is then carried to the anterior pituitary gland, where it 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.[citation needed]
Somatostatin is also produced by several other 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, populations of somatostatin neurons occur in the arcuate nucleus,[15] the hippocampus,[16] and the brainstem nucleus of the solitary tract.[citation needed]
Functions
D cell is visible at upper right, and somatostatin is represented by middle arrow pointing left
Somatostatin is classified as an inhibitory hormone,[7] and is induced by low pH.[citation needed] Its actions are spread to different parts of the body. Somatostatin release is inhibited by the Vagus nerve.[17]
Octreotide (brand name Sandostatin, Novartis Pharmaceuticals) is an octapeptide that mimics natural somatostatin pharmacologically, though is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone, and has a much longer half-life (about 90 minutes, compared to 2–3 minutes for somatostatin). Since it is absorbed poorly from the gut, it is administered parenterally (subcutaneously, intramuscularly, or intravenously). It is indicated for symptomatic treatment of carcinoid syndrome and acromegaly.[22][23] It is also finding increased use in polycystic diseases of the liver and kidney.
Lanreotide (Somatuline, Ipsen Pharmaceuticals) is a medication used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome. It is a long-acting analog of somatostatin, like octreotide. It is available in several countries, including the United Kingdom, Australia, and Canada, and was approved for sale in the United States by the Food and Drug Administration on August 30, 2007.
Pasireotide, sold under the brand name Signifor, is an orphan drug approved in the United States and the European Union for the treatment of Cushing's disease in patients who fail or are ineligible for surgical therapy. It was developed by Novartis. Pasireotide is somatostatin analog with a 40-fold increased affinity to somatostatin receptor 5 compared to other somatostatin analogs.
Evolutionary history
Six somatostatin genes have been discovered in vertebrates. The current proposed history as to how these six genes arose is based on the three whole-genome duplication events that took place in vertebrate evolution along with local duplications in teleost fish. An ancestral somatostatin gene was duplicated during the first whole-genome duplication event (1R) to create SS1 and SS2. These two genes were duplicated during the second whole-genome duplication event (2R) to create four new somatostatin genes:SS1, SS2, SS3, and one gene that was lost during the evolution of vertebrates. Tetrapods retained SS1 (also known as SS-14 and SS-28) and SS2 (also known as cortistatin) after the split in the Sarcopterygii and Actinopterygii lineage split. In teleost fish, SS1, SS2, and SS3 were duplicated during the third whole-genome duplication event (3R) to create SS1, SS2, SS4, SS5, and two genes that were lost during the evolution of teleost fish. SS1 and SS2 went through local duplications to give rise to SS6 and SS3.[9]
^ abNelson DL, Cox M (2021). Lehninger Principles of Biochemistry (8 ed.). Austin. ISBN978-1-319-22800-2. OCLC1243000176. The binding of somatostatin to its receptor in the pancreas leads to activation of an inhibitory G protein, or Gi, structurally homologous to Gs, that inhibits adenylyl cyclase and lowers [cAMP]. In this way, somatostatin inhibits the secretion of several hormones, including glucagon((cite book)): CS1 maint: location missing publisher (link)
^ abcLiu Y, Lu D, Zhang Y, Li S, Liu X, Lin H (September 2010). "The evolution of somatostatin in vertebrates". Gene. 463 (1–2): 21–8. doi:10.1016/j.gene.2010.04.016. PMID20472043.
^Holst JJ, Skak-Nielsen T, Orskov C, Seier-Poulsen S (August 1992). "Vagal control of the release of somatostatin, vasoactive intestinal polypeptide, gastrin-releasing peptide, and HCl from porcine non-antral stomach". Scandinavian Journal of Gastroenterology. 27 (8): 677–85. doi:10.3109/00365529209000139. PMID1359631.
^ abBowen R (2002-12-14). "Somatostatin". Biomedical Hypertextbooks. Colorado State University. Retrieved 2008-02-19.
^"Acromegaly". NIDDK. April 2012. Archived from the original on 27 August 2016. Retrieved 5 July 2021.
Further reading
Florio T, Schettini G (September 2001). "[Somatostatin and its receptors. Role in the control of cell proliferation]". Minerva Endocrinologica. 26 (3): 91–102. PMID11753230.
Panetta R, Greenwood MT, Warszynska A, Demchyshyn LL, Day R, Niznik HB, Srikant CB, Patel YC (March 1994). "Molecular cloning, functional characterization, and chromosomal localization of a human somatostatin receptor (somatostatin receptor type 5) with preferential affinity for somatostatin-28". Molecular Pharmacology. 45 (3): 417–27. PMID7908405.
Demchyshyn LL, Srikant CB, Sunahara RK, Kent G, Seeman P, Van Tol HH, Panetta R, Patel YC, Niznik HB (June 1993). "Cloning and expression of a human somatostatin-14-selective receptor variant (somatostatin receptor 4) located on chromosome 20". Molecular Pharmacology. 43 (6): 894–901. PMID8100352.
Barnea A, Roberts J, Ho RH (January 1999). "Evidence for a synergistic effect of the HIV-1 envelope protein gp120 and brain-derived neurotrophic factor (BDNF) leading to enhanced expression of somatostatin neurons in aggregate cultures derived from the human fetal cortex". Brain Research. 815 (2): 349–57. doi:10.1016/S0006-8993(98)01098-1. PMID9878821. S2CID21793593.
Brakch N, Lazar N, Panchal M, Allemandou F, Boileau G, Cohen P, Rholam M (February 2002). "The somatostatin-28(1-12)-NPAMAP sequence: an essential helical-promoting motif governing prosomatostatin processing at mono- and dibasic sites". Biochemistry. 41 (5): 1630–9. doi:10.1021/bi011928m. PMID11814357.
Simonetti M, Di BC (February 2002). "Structural motifs in the maturation process of peptide hormones. The somatostatin precursor. I. A CD conformational study". Journal of Peptide Science. 8 (2): 66–79. doi:10.1002/psc.370. PMID11860030. S2CID20438890.
External links
Overview of all the structural information available in the PDB for UniProt: P61278 (Somatostatin) at the PDBe-KB.
