Biology:Somatostatin receptor 2

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Somatostatin receptor type 2 is a protein that in humans is encoded by the SSTR2 gene.[1]

The SSTR2 gene is located on chromosome 17 on the long arm in position 25.1 in humans.[2] It is also found in most other vertebrates.[3]

The somatostatin receptor 2 (SSTR2), which belongs to the G-protein coupled receptor family, is a protein which is most highly expressed in the pancreas (both alpha- and beta-cells), but also in other tissues such as the cerebrum and kidney and in lower amount in the jejunum, colon and liver.[4][5][6] In the pancreas, after binding to somatostatin, it inhibits the secretion of peptide hormones from pancreatic islets.[4] During development, it stimulates neuronal migration and axon outgrowth.[4]

The somatostatin receptor 2 is expressed in most tumors.[7] Patients with neuroendocrine tumors that over-express the somatostatin receptor 2 have an improved prognosis.[8] The over expression of SSTR2 in tumors can be exploited to selectively deliver radio-peptides to tumors to either detect or destroy them.[9] Somatostatin receptor 2 also has the ability to stimulate apoptosis in many cells including cancer cells.[10] The somatostatin receptor 2 is also being looked at as a possible target in cancer treatment for its ability to inhibit tumor growth.[11]

Function

The gene for somatostatin receptor 2, SSTR2 for short, is responsible for making a receptor for the signalling peptide, somatostatin (SST). Production occurs in the central nervous system, especially the hypothalamus, as well as the digestive system, and pancreas.[12] SSTR2 is a receptor for somatostatin-14 and -28 respectively. The numbers 14 and 28 represent the amount of amino acids in each protein sequence.[12] All somatostatin receptors including SSTR2 may have different specific functions, but all fall under the same receptor super family, the G-protein binding family and all of which are a major inhibitor for other hormones.[13] For all somatostatin inhibitors, somatostatin-14 and -28 work by binding to the receptor with the help of a G-protein. This inhibits adenylyl cyclase and calcium channels. These proteins are released in various parts of the human body and vary in the amount emitted from each organ system. In secretory cells this protein is in a greater volume compared to amount released from activated immune and inflammatory cells. These proteins have a tendency of being emitted in response to items such as: ions, nutrients, neuropeptides, neurotransmitters, hormones, growth factors, and cytokines.[14]

In general, somatostatin can put a cell in cycle arrest using the phosphotyrosine phosphatase dependent regulation of nitrogen-activated protein kinase, this process can lead to a halt in the cell cycle or apoptosis of the cell and is used as a tumor suppressor in the genome. This hormone is also known to perform agonist-dependent endocytosis, which allows a cell to take in receptors, ions, and other molecules.[14]

Because this protein is found in multiple organs, it has a different specific role in each organ or organ system. A major function of the protein made by the gene SSTR2 is pancreatic interaction with the alpha and beta cells. In the delta cells of the pancreas, this hormone inhibits the secretion of both glucagon and insulin in the alpha and beta cells when stimulated by basic nutrients like sugars, proteins, and fats.[15] In fact, this protein, is the dominant one out of all of the somatostatins in the pancreas. In the stomach, it reduces activity of the digestive tract by inhibiting secretion of gastric acid, pepsin, bile, and colonic acid when in the presence of luminal nutrients; all of these secretions are needed for proper digestion. It also represses motor activity in the gut by blocking segmentation of the intestines, gallbladder contraction, and emptying of the bowels. This inhibition by somatostatin allows the body to uptake the maximum amount of nutrients in the digestive system.[16] Along with the gut and pancreas, SSTR2 also inhibits secretion of neurotransmitters in the central and peripheral nervous system. These hormones include dopamine, norepinephrine, thyrotropin-releasing hormone, and corticotropin-releasing hormone. Many of these hormones help the body maintain homeostasis or react properly to a stimulus such as something pleasurable or a stress in the environment. Because of which, the receptors for somatostatin type 2 impact the body's locomotor, sensory, autonomic, and cognitive functions.

Interactions

Somatostatin receptor 2 has been shown to interact with SHANK2.[17]

Clinical significance

The somatostatin hormone itself can negatively affect the uptake of hormones in the body and may play a role in some hormonal conditions. Somatostatin 2 receptors have been found in concentration on the surface of tumor cells, particularly those associated with the neuroendocrine system where the overexpression of somatostatin can lead to many complications[18][19] Due to this, these receptors are considered a prospective aid for the detection of tumors, especially in patients who present with conditions like hypothyroidism and Cushing's syndrome.[20][21] A synthetic version of the somatostatin hormone, octreotide, has been successfully used in combination with radio-peptide tracers to locate adrenal gland tumors through scintigraphic imaging.[22] A similar method may be utilized to carry and more accurately administer radioactive treatments to tumors.[22] Octreotide and other analogs are preferred for this use due to their possessing of an extended half life compared to the naturally-occurring hormone allowing for more flexibility when used for such treatments.[21]

The association of somatostatin 2 receptors on tumors has also led to the suggestion of possible alternatives to current tumor treatment methods. The binding of synthetic somatostatin hormones such as octreotide to receptors has been seen to reduce the production of hormones and is now being considered for use in the treatment of some pituitary tumors. One group suggests that the treatment method would be particularly effective against thyrotropin-secreting pituitary adenomas (TSHomas), though further inquiries and clinical trials are needed.[20]

SSTR2 is also being investigated for its potential use as a reporter gene for the visualization of regional gene expression. One study tested this by comparing the PET/CT and light imaging results of laboratory rats' musculature obtained through the use of a human somatostatin receptor 2 vector and a control luciferase vector.[22] The study suggests that somatostatin receptor genes could be an effective substitute for the current viral-based vectors since the sstr genes elicits less of an immune response and has overall been well tolerated by the trial patients' bodies. This form of treatment may be especially useful for the study of gene expression in larger mammals whose larger body mass may obstruct clear visualization of deep tissue areas.[22] The use of sstr2 and sstr5 as biomarkers to track the progress of and treat neuroendocrine tumors displaying circulating tumor cells is also being investigated due to these cells' somatostatin receptor gene expressivity.[19]

Therapeutic targeting

Most pituitary adenomas express SSTR2, but other somatostatin receptors are also found.[23] Somatostatin analogs (i.e. Octreotide, Lanreotide ) are used to stimulate these receptors, and thus to inhibit further tumor proliferation.[24]

Discovery

There is a group of somatostatin receptors called the somatostatin receptor family. All of the members of the somatostatin receptor family are proteins that sit on the surface of the cell membrane and are responsible for the communication between cells.[25] In 1972,[26] scientists were on the trek to discover more information on the hypothalamus and its "release factors."[26] Studies showed patterns of inhibitory activity of the hypothalamus release factors which led scientists in the direction to discover somatostatin, known as the somatropin release-inhibiting factor, or SRIF. We now know that the SRIF is located at 3q28 (long arm of the third chromosome at the twenty-eighth position) in humans.[26] Peering into location 3q28, the majority of proteins code for the pancreas, ovaries, and prostate along with other components of the endocrine system and nervous system,[27] so it can be drawn that the receptor family has great influence among these systems. The family was first discovered in a segment of a rat's pituitary gland known as the tumor cell line.[28] A cell line is grown as a culture under controlled conditions, so the first discovery was found by culturing these cells in controlled conditions and in an environment outside of its norm. There, researchers found that the tumor cell line expresses a cell dividing inhibitor known as the transforming growth factor beta (TGF-beta)[29] and also acts as an inhibitor to the milk producing hormone in female mammals, prolactin, and growth hormones. Researchers studied the activity of the receptors by conducting an assay with Ligand binding studies,[28] which basically means they were conducting studies to see how prevalent the binding of the receptors occurred.[30][28] Differences in how prevalently they receptors bonded revealed the existence of multiple receptors.[28] Based on the ligand binding affinity and the receptors' signaling mechanisms, the receptor family was divided into 2 different groups, and within those groups, 5 subgroups. The group with a high affinity binding were classified under the SRIF1 group with sst2, sst3, and sst5 in the subgroup, while the receptors with low affinity binding were classified under the SRIF2 group with sst1 and sst4 in the subgroup. Manipulations with the somatostatin receptors are used for many therapies in both the endocrine and nervous system, and now that we know the groups and subgroups of the receptor family, therapy treatment is much more efficient and effective. For example, as you continue reading the article, you will notice the importance and advancements of oncology and tumor treatments, as well as other ways the somatostatin receptors are working and advancing the world of medicine.[31]

The somatostatin receptor 2 is found on the chromosome 17.[32] Information was gathered and determined from a sample of individuals, and conclusions were drawn upon location and other information regarding the SSRT2 protein.[32]

Gene: SSTR2
Title: somatostatin receptor 2
Location: 73,165,021..73,171,955
Length: 6,935 nt
[Positional Info]
NC_000017.11 position: 73,168,608
Gene position: 3,588

Isoforms

Like other proteins, the somatostatin receptor 2 also has variants. Somatostatin receptor 2 exists in two isoforms that are different in carboxy-terimini compositions and size. Alternative splicing of the somatostatin receptor 2 mRNA resulted in two variants, somatostatin receptor 2a (SSTR2A) and somatostatin receptor 2b (SSTR2B). In a rodent, somatostatin receptor 2a is longer compared to the shorter somatostatin receptor 2b. Isoform a and isoform b sequences are different, beginning at the C-terminal regulatory domains.[33] Studies have shown that carboxy-terminal splicing has occurred in many other transmembrane receptors, along with prostaglandin E receptor (EP3).[34] These variants, SST2A receptor and SST2B receptor are seen in some brain and spinal cord areas in a rodent.[35] Somatostatin receptor 2a has a shorter transcript, but is longer than somatostatin receptor 2b and has a unique C- terminus compared to Somatostatin Receptor 2b.[34] SSTRB receptor has approximately 300 nucleotides between carboxyl terminus and transmembrane segments fewer than the original Somatostatin receptor 2. SST2A receptor is made up of 369 amino acids and 346 amino acids make up the SST2B receptor.[36] Somatostatin receptor 2a and somatostatin receptor 2b were found in the medulla oblongata, mesencephalon, testis, cortex, hypothalamus, hippocampus and pituitary of a rodent, using reverse transcription polymerase chain reaction (RT-PCR).[33] Somatostatin receptor 2a is highly evident in the cortex, but the somatostatin receptor 2b is not seen as much. The medulla oblongata shows equal amounts of the two variants being expressed. The Somatostatin receptor 2a was found mostly in far down layers of the cerebral cortex, in the human brain. This variant of the Somatostatin receptor was found with the use of immunohistochemistry.[37] The difference in ratios of the isoforms imply a tissue-specific control of transcription. Somatostatin receptor 2b is not shown expressed without somatostatin receptor 2a in the brain.[33]

References

  1. ↑ "Human somatostatin receptor genes: localization to human chromosomes 14, 17, and 22 and identification of simple tandem repeat polymorphisms". Genomics 15 (2): 449–52. February 1993. doi:10.1006/geno.1993.1088. PMID 8449518. 
  2. ↑ "SSTR2 Symbol Report". HUGO Gene Nomenclature Committee. https://www.genenames.org/cgi-bin/gene_symbol_report?hgnc_id=HGNC:11331. 
  3. ↑ "ortholog_gene_6752[group – Gene"]. NCBI. https://www.ncbi.nlm.nih.gov/gene/?Term=ortholog_gene_6752%5Bgroup%5D. 
  4. ↑ 4.0 4.1 4.2 Universal protein resource accession number P30874 for "SSTR2 – Somatostatin receptor type 2 – Homo sapiens (Human)" at UniProt.
  5. ↑ "SSTR2 Gene". GeneCards Human Gene Database Gene. https://www.genecards.org/cgi-bin/carddisp.pl?gene=SSTR2. 
  6. ↑ "SSTR2 somatostatin receptor 2 [Homo sapiens (human) – Gene"]. NCBI. https://www.ncbi.nlm.nih.gov/gene?cmd=Retrieve&dopt=full_report&list_uids=6752. 
  7. ↑ "Somatostatin receptor sst1-sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands". European Journal of Nuclear Medicine 28 (7): 836–46. July 2001. doi:10.1007/s002590100541. PMID 11504080. 
  8. ↑ "Somatostatin receptor expression indicates improved prognosis in gastroenteropancreatic neuroendocrine neoplasm, and octreotide long-acting release is effective and safe in Chinese patients with advanced gastroenteropancreatic neuroendocrine tumors". Oncology Letters 13 (3): 1165–1174. March 2017. doi:10.3892/ol.2017.5591. PMID 28454229. 
  9. ↑ "SSTR2 – Clinical: Somatostatin Receptor 2 (SSTR2), Immunostain, Technical Component Only". https://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/113597. 
  10. ↑ "Activation of human somatostatin receptor 2 promotes apoptosis through a mechanism that is independent from induction of p53" (in en). Cellular Physiology and Biochemistry 12 (1): 31–8. 2002. doi:10.1159/000047824. PMID 11914546. 
  11. ↑ "Somatostatin Receptors in Lung Cancer: From Function to Molecular Imaging and Therapeutics". Journal of Lung Cancer 10 (2): 69–76. 2011. doi:10.6058/jlc.2011.10.2.69. PMID 25663834. 
  12. ↑ 12.0 12.1 "SSTR2 is the functionally dominant somatostatin receptor in human pancreatic β- and α-cells". American Journal of Physiology. Endocrinology and Metabolism 303 (9): E1107-16. November 2012. doi:10.1152/ajpendo.00207.2012. PMID 22932785. 
  13. ↑ "Somatostatin" (in en). http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/otherendo/somatostatin.html. 
  14. ↑ 14.0 14.1 "Somatostatin and its receptor family". Frontiers in Neuroendocrinology 20 (3): 157–98. July 1999. doi:10.1006/frne.1999.0183. PMID 10433861. 
  15. ↑ "Expression of somatostatin and somatostatin receptor subtypes 1-5 in human normal and diseased kidney". The Journal of Histochemistry and Cytochemistry 56 (8): 733–43. August 2008. doi:10.1369/jhc.2008.950998. PMID 18443363. 
  16. ↑ Carroll, Robert G. (2007). "Endocrine System". Elsevier's Integrated Physiology. Elsevier. pp. 157–176. doi:10.1016/b978-0-323-04318-2.50019-4. ISBN 9780323043182. 
  17. ↑ "Somatostatin receptor interacting protein defines a novel family of multidomain proteins present in human and rodent brain". The Journal of Biological Chemistry 274 (46): 32997–3001. November 1999. doi:10.1074/jbc.274.46.32997. PMID 10551867. 
  18. ↑ "Joint Program in Nuclear Medicine". http://www.med.harvard.edu/jpnm/tf94_95/nov1/writeupnov1.html. 
  19. ↑ 19.0 19.1 "Expression of somatostatin receptors 2 and 5 in circulating tumour cells from patients with neuroendocrine tumours". British Journal of Cancer 115 (12): 1540–1547. December 2016. doi:10.1038/bjc.2016.377. PMID 27875519. 
  20. ↑ 20.0 20.1 "Clinical Importance of Somatostatin Receptor 2 (SSTR2) and Somatostatin Receptor 5 (SSTR5) Expression in Thyrotropin-Producing Pituitary Adenoma (TSHoma)". Medical Science Monitor 23: 1947–1955. April 2017. doi:10.12659/MSM.903377. PMID 28434012. 
  21. ↑ 21.0 21.1 "The biology and clinical relevance of somatostatin receptor scintigraphy in adrenal tumor management". The Yale Journal of Biology and Medicine 70 (5–6): 565–75. 1997. PMID 9825485. 
  22. ↑ 22.0 22.1 22.2 22.3 "PET/CT imaging of human somatostatin receptor 2 (hsstr2) as reporter gene for gene therapy.". Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment 569 (2): 509–11. December 2006. doi:10.1016/j.nima.2006.08.161. Bibcode: 2006NIMPA.569..509H. 
  23. ↑ "Somatostatin receptor subtype gene expression in pituitary adenomas". The Journal of Clinical Endocrinology and Metabolism 80 (4): 1386–92. April 1995. doi:10.1210/jcem.80.4.7714115. PMID 7714115. 
  24. ↑ "Control of pituitary adenoma cell proliferation by somatostatin analogs, dopamine agonists and novel chimeric compounds". European Journal of Endocrinology 156 (Suppl 1): S29-35. April 2007. doi:10.1530/eje.1.02352. PMID 17413185. https://iris.unife.it/bitstream/11392/521543/1/reprint%20EJE2007.pdf. 
  25. ↑ "The Virtual Cell Textbook – Cell Biology". https://www.ibiblio.org/virtualcell/textbook/chapter3/cmf3.htm. 
  26. ↑ 26.0 26.1 26.2 "Somatostatin receptors". Biochimica et Biophysica Acta (BBA) - Biomembranes 1616 (1): 1–84. September 2003. doi:10.1016/S0005-2736(03)00235-9. PMID 14507421. 
  27. ↑ "Chromosome 3". http://atlasgeneticsoncology.org/Bands/3q28.html. 
  28. ↑ 28.0 28.1 28.2 28.3 "Somatostatin receptors". IUPHAR/BPS Guide to Pharmacology. http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=61. 
  29. ↑ "A rat pituitary tumor cell line (GH3) expresses type I and type II receptors and other cell surface binding protein(s) for transforming growth factor-beta". The Journal of Biological Chemistry 270 (2): 770–4. January 1995. doi:10.1074/jbc.270.2.770. PMID 7822309. 
  30. ↑ "Definition of Assay" (in en). MedicineNet. https://www.medicinenet.com/script/main/art.asp?articlekey=8412. 
  31. ↑ "Prolactin". You and Your Hormones. Society for Endocrinology. http://www.yourhormones.info/hormones/prolactin/. 
  32. ↑ 32.0 32.1 "SSTR2 somatostatin receptor 2 [Homo sapiens (human)"]. NCBI. https://www.ncbi.nlm.nih.gov/gene/6752. 
  33. ↑ 33.0 33.1 33.2 "mRNA distribution of two isoforms of somatostatin receptor 2 (mSSTR2A and mSSTR2B) in mouse brain". Brain Research. Molecular Brain Research 27 (1): 45–50. November 1994. doi:10.1016/0169-328X(94)90182-1. PMID 7877453. 
  34. ↑ 34.0 34.1 "Differential distribution of alternatively spliced somatostatin receptor 2 isoforms (sst2A and sst2B) in rat spinal cord". Neuroscience Letters 257 (1): 37–40. November 1998. doi:10.1016/s0304-3940(98)00803-9. PMID 9857960. 
  35. ↑ "Multiple gene transcripts of the somatostatin receptor SSTR2: tissue selective distribution and cAMP regulation". Biochemical and Biophysical Research Communications 192 (1): 288–94. April 1993. doi:10.1006/bbrc.1993.1412. PMID 8386508. 
  36. ↑ Møller, Lars Neisig; Stidsen, Carsten Enggaard; Hartmann, Bolette; Holst, Jens Juul (2003-09-22). "Somatostatin receptors". Biochimica et Biophysica Acta (BBA) - Biomembranes 1616 (1): 1–84. doi:10.1016/S0005-2736(03)00235-9. ISSN 0005-2736. PMID 14507421. 
  37. ↑ "Characterisation of somatostatin sst2 receptor splice variants". Journal of Physiology, Paris 94 (3–4): 217–37. 2000. doi:10.1016/S0928-4257(00)00207-2. PMID 11088000. 

Further reading

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