Somatostatin

Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Somatostatin inhibits insulin and glucagon secretion.[5][6]

Not to be confused with Somatocrinin or Somatomedin.
SST
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSST, SMST, somatostatin, Somatostatin, Somatostatin, SST1
External IDsOMIM: 182450 MGI: 98326 HomoloGene: 819 GeneCards: SST
Orthologs
SpeciesHumanMouse
Entrez

6750

20604

Ensembl

ENSG00000157005

ENSMUSG00000004366

UniProt

P61278

P60041

RefSeq (mRNA)

NM_001048

NM_009215

RefSeq (protein)

NP_001039

NP_033241

Location (UCSC)Chr 3: 187.67 – 187.67 MbChr 16: 23.71 – 23.71 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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]

Nomenclature

Synonyms of "somatostatin" include:

  • growth hormone–inhibiting hormone (GHIH)
  • growth hormone release–inhibiting hormone (GHRIH)
  • somatotropin release–inhibiting factor (SRIF)
  • somatotropin release–inhibiting hormone (SRIH)

Production

Digestive system

Somatostatin is secreted by delta cells at several locations in the digestive system, namely the pyloric antrum, the duodenum and the pancreatic islets.[14]

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.

Brain
Sst is expressed in interneurons in the telencephalon of the embryonic day 15.5 mouse. Allen Brain Atlases
Sst expression in the adult 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.

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.

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. Its actions are spread to different parts of the body. Somatostatin release is inhibited by the Vagus nerve.[17]

Anterior pituitary

In the anterior pituitary gland, the effects of somatostatin are:

Gastrointestinal system
  • Somatostatin is homologous with cortistatin (see somatostatin family) and suppresses the release of gastrointestinal hormones
  • Decreases the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine[18]
  • Suppresses the release of pancreatic hormones
    • Somatostatin release is triggered by the beta cell peptide urocortin3 (Ucn3) to inhibit insulin release.[20][21]
    • Inhibits the release of glucagon[20][6]
  • Suppresses the exocrine secretory action of the pancreas

Synthetic substitutes

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]

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000157005 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000004366 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "somatostatin". Encyclopædia Britannica. Encyclopædia Britannica Online. Encyclopædia Britannica Inc., 2016. Web. 04 mag. 2016 <http://www.britannica.com/science/somatostatin>.
  6. Nelson DL, Cox M (2021). Lehninger Principles of Biochemistry (8 ed.). Austin. ISBN 978-1-319-22800-2. OCLC 1243000176. 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)
  7. Costoff A. "Sect. 5, Ch. 4: Structure, Synthesis, and Secretion of Somatostatin". Endocrinology: The Endocrine Pancreas. Medical College of Georgia. p. 16. Archived from the original on April 5, 2008. Retrieved 2008-02-19.
  8. "somatostatin preproprotein [Homo sapiens]". NCBI Reference Sequence. National Center for Biotechnology Information Support Center (NCBI).
  9. Liu 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. PMID 20472043.
  10. Gahete MD, Cordoba-Chacón J, Duran-Prado M, Malagón MM, Martinez-Fuentes AJ, Gracia-Navarro F, Luque RM, Castaño JP (July 2010). "Somatostatin and its receptors from fish to mammals". Annals of the New York Academy of Sciences. 1200 (1): 43–52. Bibcode:2010NYASA1200...43G. doi:10.1111/j.1749-6632.2010.05511.x. PMID 20633132. S2CID 23346102.
  11. "Entrez Gene: Somatostatin".
  12. Shen LP, Pictet RL, Rutter WJ (August 1982). "Human somatostatin I: sequence of the cDNA". Proceedings of the National Academy of Sciences of the United States of America. 79 (15): 4575–9. Bibcode:1982PNAS...79.4575S. doi:10.1073/pnas.79.15.4575. PMC 346717. PMID 6126875.
  13. Shen LP, Rutter WJ (April 1984). "Sequence of the human somatostatin I gene". Science. 224 (4645): 168–71. Bibcode:1984Sci...224..168S. doi:10.1126/science.6142531. PMID 6142531.
  14. Boron WF, Boulpaep EL (2012). Medical Physiology (2nd ed.). Philadelphia, PA: Elsevier. ISBN 9781437717532.
  15. Minami, Shiro; Kamegai, Jun; Sugihara, Hitoshi; Suzuki, Nobuchika; Wakabayashi, Ichiji (1998). "Growth Hormone Inhibits Its Own Secretion by Acting on the Hypothalamus through Its Receptors on Neuropeptide Y Neurons in the Arcuate Nucleus and Somatostatin Neurons in the Periventricular Nucleus". Endocrine Journal. 45: S19-26. doi:10.1507/endocrj.45.Suppl_S19. PMID 9790225. Retrieved 10 January 2021.
  16. Stefanelli, Thomas; Bertollini, Cristina; Lüscher, Christian; Muller, Dominique; Mendez, Pablo (February 2016). "Hippocampal Somatostatin Interneurons Control the Size of Neuronal Memory Ensembles". Neuron. 89 (5): 1074–1085. doi:10.1016/j.neuron.2016.01.024. PMID 26875623.
  17. 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. PMID 1359631.
  18. Bowen R (2002-12-14). "Somatostatin". Biomedical Hypertextbooks. Colorado State University. Retrieved 2008-02-19.
  19. First Aid for the USMLE Step 1, 2010. Page 286.
  20. Costoff A. "Sect. 5, Ch. 4: Structure, Synthesis, and Secretion of Somatostatin". Endocrinology: The Endocrine Pancreas. Medical College of Georgia. p. 17. Archived from the original on March 31, 2008. Retrieved 2008-02-19.
  21. van der Meulen T, Donaldson CJ, Cáceres E, Hunter AE, Cowing-Zitron C, Pound LD, Adams MW, Zembrzycki A, Grove KL, Huising MO (July 2015). "Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion". Nature Medicine. 21 (7): 769–76. doi:10.1038/nm.3872. PMC 4496282. PMID 26076035.
  22. "Carcinoid Tumors and Syndrome". The Lecturio Medical Concept Library. Retrieved 5 July 2021.
  23. "Acromegaly". NIDDK. April 2012. Archived from the original on 27 August 2016. Retrieved 5 July 2021.

Further reading
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