Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a

peptide hormone Peptide hormones or protein hormones are hormones whose molecules are peptide, or proteins, respectively. The latter have longer amino acid chain lengths than the former. These hormones have an effect on the endocrine system of animals, including h ...

that regulates the

endocrine system The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neu ...

and affects

neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...

and

cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation re ...

via interaction with

G protein-coupled G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

somatostatin receptors Somatostatin receptors are receptors for the ligand somatostatin, a small neuropeptide associated with neural signaling, particularly in the post-synaptic response to NMDA receptor co-stimulation/activation. Somatostatin is encoded by a CRE ...

and inhibition of the release of numerous secondary hormones. Somatostatin inhibits insulin and glucagon secretion. Somatostatin has two active forms produced by the alternative cleavage of a single preproprotein: one consisting of 14

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

s (shown in infobox to right), the other consisting of 28 amino acids. Among the

vertebrates Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...

, there exist six different somatostatin genes that have been named ''SS1, SS2, SS3, SS4, SS5'' and ''SS6''.

Zebrafish The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family ( Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ...

have all six. The six different genes, along with the five different

, allow somatostatin to possess a large range of functions. Humans have only one somatostatin gene, ''SST''.

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 Delta cells (δ-cells or D cells) are somatostatin-producing cell (biology), cells. They can be found in the stomach, intestine and the pancreatic islets. Delta cells comprise ca 5% of the cells in the islets but may interact with many more islet ...

at several locations in the digestive system, namely the

pyloric antrum The pylorus ( or ), or pyloric part, connects the stomach to the duodenum. The pylorus is considered as having two parts, the ''pyloric antrum'' (opening to the body of the stomach) and the ''pyloric canal'' (opening to the duodenum). The ''pylori ...

, the

duodenum The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...

and the

pancreatic islets The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% of ...

. Somatostatin released in the

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 Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse ove ...

manner. In the stomach, somatostatin acts directly on the acid-producing

parietal cells Parietal cells (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor. These cells are located in the gastric glands found in the lining of the fundus and body regions of the ...

via a G-protein coupled receptor (which inhibits adenylate cyclase, thus effectively antagonising the stimulatory effect of histamine) to reduce acid secretion. Somatostatin can also indirectly decrease stomach acid production by preventing the release of other hormones, including

gastrin Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas. Gastrin ...

and

histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...

which effectively slows down the digestive process.

Brain

Somatostatin is produced by

neuroendocrine Neuroendocrine cells are cells that receive neuronal input (through neurotransmitters released by nerve cells or neurosecretory cells) and, as a consequence of this input, release messenger molecules ( hormones) into the blood. In this way they b ...

neurons of the

ventromedial nucleus The ventromedial nucleus of the hypothalamus (VMN, also sometimes referred to as the ventromedial hypothalamus, VMH) is a Nucleus (neuroanatomy), nucleus of the hypothalamus. "The ventromedial hypothalamus (VMH) is a distinct morphological nucleu ...

of the

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...

. These neurons project to the

median eminence The median eminence, part of the inferior boundary of the hypothalamus in the brain, is attached to the infundibulum. The median eminence is a small swelling on the tuber cinereum, posterior to and atop the pituitary stalk; it lies in the area rou ...

, where somatostatin is released from neurosecretory nerve endings into the hypothalamohypophysial system through neuron axons. Somatostatin is then carried to the

anterior pituitary gland A major organ of the endocrine system, the anterior pituitary (also called the adenohypophysis or pars anterior) is the glandular, anterior lobe that together with the posterior lobe (posterior pituitary, or the neurohypophysis) makes up the pi ...

, where it inhibits the secretion of

growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in h ...

from

somatotrope Somatotropes (from the Greek ''sōmat'' meaning "body" and ''tropikós'' meaning "of or pertaining to a turn or change") are cells in the anterior pituitary that produce growth hormone. Structure Somatotropic cells constitute about 30−40% of ant ...

cells. The somatostatin neurons in the periventricular nucleus mediate negative feedback effects of

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 The arcuate nucleus of the hypothalamus (also known as ARH, ARC, or infundibular nucleus) is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several ...

, the

hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...

, and the brainstem

nucleus of the solitary tract In the human brainstem, the solitary nucleus, also called nucleus of the solitary tract, nucleus solitarius, and nucleus tractus solitarii, (SN or NTS) is a series of purely sensory nuclei (clusters of nerve cell bodies) forming a vertical column ...

Functions

Somatostatin is classified as an

inhibitory An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential.Purves et al. Neuroscience. 4th ed. Sunderland (MA): Sinauer Associates, Incorporated; 2008. ...

hormone, and is induced by low pH. Its actions are spread to different parts of the body. Somatostatin release is inhibited by the

Vagus nerve The vagus nerve, also known as the tenth cranial nerve, cranial nerve X, or simply CN X, is a cranial nerve that interfaces with the parasympathetic control of the heart, lungs, and digestive tract. It comprises two nerves—the left and right ...

Anterior pituitary

In the

, the effects of somatostatin are: * Inhibiting the release of growth hormone (GH) (thus opposing the effects of

growth hormone–releasing hormone Growth hormone–releasing hormone (GHRH), also known as somatocrinin or by #Nomenclature, several other names in its endogeny (biology), endogenous forms and as somatorelin (International Nonproprietary Name, INN) in its pharmaceutical, pharmace ...

(GHRH)) * Inhibiting the release of

thyroid-stimulating hormone Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of ...

(TSH) * Inhibiting

adenylyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

in parietal cells * Inhibiting the release of

prolactin Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pit ...

(PRL)

Gastrointestinal system

* Somatostatin is homologous with cortistatin (see

somatostatin family The somatostatin family is a protein family with somatostatin as titular member, a hormone which inhibits the release of the pituitary somatotropin (growth hormone) and inhibits the release of glucagon and insulin from the pancreas of fasted a ...

) and suppresses the release of

gastrointestinal hormone The gastrointestinal hormones (or gut hormones) constitute a group of hormones secreted by enteroendocrine cells in the stomach, pancreas, and small intestine that control various functions of the digestive organs. Later studies showed that most o ...

s * Decreases the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine * Suppresses the release of pancreatic hormones ** Somatostatin release is triggered by the beta cell peptide urocortin3 (Ucn3) to inhibit

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

release. ** Inhibits the release of glucagon * Suppresses the exocrine secretory action of the pancreas

Synthetic substitutes

Octreotide Octreotide, sold under the brand name Sandostatin among others, is an octapeptide that mimics natural somatostatin pharmacologically, though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone. It was ...

(brand name Sandostatin,

Novartis Pharmaceuticals Novartis AG is a Swiss-American multinational corporation, multinational pharmaceutical company, pharmaceutical corporation based in Basel, Switzerland and Cambridge, Massachusetts, United States (global research).name="novartis.com">https://w ...

) 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 Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...

(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 Symptomatic treatment, supportive care, supportive therapy, or palliative treatment is any medical therapy of a disease that only affects its symptoms, not the underlying cause. It is usually aimed at reducing the signs and symptoms for the comfor ...

carcinoid syndrome Carcinoid syndrome is a paraneoplastic syndrome comprising the signs and symptoms that occur secondary to carcinoid tumors. The syndrome includes flushing and diarrhea, and less frequently, heart failure, vomiting and bronchoconstriction. It is ...

and

acromegaly Acromegaly is a disorder that results from excess growth hormone (GH) after the growth plates have closed. The initial symptom is typically enlargement of the hands and feet. There may also be an enlargement of the forehead, jaw, and nose. Other ...

. It is also finding increased use in polycystic diseases of the liver and kidney.

Lanreotide Lanreotide, sold under the brand name Somatuline among others, is a medication used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome. It is a long-acting analogue of somatostatin, like ...

(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 Analog or analogue may refer to: Computing and electronics * Analog signal, in which information is encoded in a continuous variable ** Analog device, an apparatus that operates on analog signals *** Analog electronics, circuits which use 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 Pasireotide, sold under the brand name Signifor, is an orphan drug approved in the United States and the European Union Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is ackno ...

, sold under the brand name Signifor, is an

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

approved in the United States and the European Union for the treatment of

Cushing's disease Cushing's disease is one cause of Cushing's syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary (secondary hypercortisolism). This is most often as a result of a pituitary adenoma (speci ...

in patients who fail or are ineligible for surgical therapy. It was developed by

Novartis Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...

. Pasireotide is somatostatin

with a 40-fold increased affinity to

somatostatin receptor 5 Somatostatin receptor type 5 is a protein that in humans is encoded by the ''SSTR5'' gene. Somatostatin acts at many sites to inhibit the release of many hormones and other secretory proteins. The biological effects of somatostatin are probably ...

compared to other somatostatin analogs.

Evolutionary history

Six somatostatin genes have been discovered in

. 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 Teleostei (; Greek ''teleios'' "complete" + ''osteon'' "bone"), members of which are known as teleosts ), is, by far, the largest infraclass in the class Actinopterygii, the ray-finned fishes, containing 96% of all extant species of fish. Tel ...

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 Tetrapods (; ) are four-limbed vertebrate animals constituting the superclass Tetrapoda (). It includes extant and extinct amphibians, sauropsids (reptiles, including dinosaurs and therefore birds) and synapsids (pelycosaurs, extinct therapsids ...

retained ''SS1'' (also known as ''SS-14'' and ''SS-28'') and ''SS2'' (also known as cortistatin) after the split in the

Sarcopterygii Sarcopterygii (; ) — sometimes considered synonymous with Crossopterygii () — is a taxon (traditionally a class or subclass) of the bony fishes known as the lobe-finned fishes. The group Tetrapoda, a mostly terrestrial superclass includi ...

and

Actinopterygii Actinopterygii (; ), members of which are known as ray-finned fishes, is a class of bony fish. They comprise over 50% of living vertebrate species. The ray-finned fishes are so called because their fins are webs of skin supported by bony or h ...

lineage split. In

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''.

References

External links

* {{GH/IGF-1 axis signaling modulators Antidiarrhoeals Endocrine system Hormones of the somatotropic axis Neuropeptides Neuroendocrinology Pancreatic hormones Somatostatin receptor agonists