THC Science

Arginine Vasopressin (AVP) Gene is a gene whose product is proteolytically cleaved to produce vasopressin (also known as antidiuretic hormone, ADH), neurophysin II, and a glycoprotein called copeptin. AVP and other AVP-like peptides are found in mammals, as well as mollusks, arthropods, nematodes, and other invertebrate species.^[1] In humans, AVP is present on chromosome 20 and plays a role in homeostatic regulation. The products of AVP have many functions that include vasoconstriction, regulating the balance of water in the body, and regulating responses to stress.^[2] Expression of AVP is regulated by the Transcription Translation Feedback Loop (TTFL), which is an important part of the circadian system that controls the expression of clock genes. AVP has important implications in the medical field as its products have significant roles throughout body.

Discovery

Vasopressin

The discovery of the AVP gene first required the discovery of one of its key products: vasopressin. In 1895, G. Oliver and E.A. Schäfer found that a substance released by the pituitary gland could elevate blood pressure. The researchers noted that intravenous injection of extracts from the pituitary gland, thyroid gland, and spleen all influence blood pressure, however the effect from the pituitary had the most significant impact.^[3] Almost thirty years later, Kamm and colleagues separated the components within the pituitary gland. Using a unique, five-step separation technique, Kamm revealed one substance associated with uterine contractions – oxytocin – and another substance associated with blood pressure – vasopressin.^[4]

Once the discovery and separation of vasopressin occurred, subsequent research on the product's structure, function, and mode of generation could take place. In 1951, Turner and colleagues uncovered the amino acid sequence behind the hormone. The amino acid structure was composed of eight amino acids, including phenylalanine, tyrosine, proline, glutamic acid, aspartic acid, glycine, arginine, and cystine. The structure was also found to include ammonia.^[5] Following this discovery, Vincent du Vigneaud was able to synthesize a synthetic form of vasopressin in a laboratory setting. Du Vigneaud specifically noted that his final product had the same activity and composition ratios as that of naturally occurring vasopressin.^[6]

AVP gene

The work on vasopressin ultimately allowed researchers to work backwards and identify the gene responsible for this product's generation. This final stage of research began when Gainer and colleagues found a precursor protein to vasopressin in 1977.^[7] The structure of the protein was subsequently discovered by Land in 1982. By sequencing complementary DNA strands that encoded for the hormone's mRNA, Land outlined the amino acid sequence of the precursor protein.^[8] Finally, one year later, Schmale, Heinsohn, and Richter isolated the AVP precursor gene in rats from their genomic library. The researchers used restriction mapping and nucleotide sequence analysis to uncover the gene's three distinct exons and the products (vasopressin, neurophysin, and glycoprotein) that each was responsible for.^[9]

Structure

The 1.85 kilobase-long AVP gene, located on chromosome 20 (20p13) contains three functional domains, including AVP, neurophysin II (NP) and a C-terminal glycopeptide called copeptin. Using restriction mapping and sequencing, the gene was found to have these domains which spanned over three exons with two intronic sequences. Exon A encodes a putative signal peptide, the arginine vasopressin hormone, and the N terminus of the NP carrier protein. Exon B, which is separated from exon A with a 1 kilobase-long intron, encodes the conserved middle portion of NP. A 227 kilobase intron separates exon B from exon C, which encodes the final domain, including the C terminus of NP and the glycoprotein. The structure of this gene has been found to be generally conserved across species, including chimpanzees, Rhesus monkeys, dogs, cows, mice, rats, chicken, zebrafish, and frogs.^[9]

Promoter region

The AVP gene promoter region consists of an E-box element located 150 residues upstreams of the transcription start site, which binds mammalian clock proteins CLOCK and BMAL1 involved in generating circadian rhythms in the suprachiasmatic nucleus (SCN).^[10] BMAL1 and CLOCK gene knockouts in the SCN (Bmal-/- and clk-/-) eliminate rhythmicity in AVP mRNA expression, confirming that binding of the protein heterodimers to the E-box element is necessary for the intrinsic circadian pattern of the AVP gene.^[11] In addition to the E-box element, the promoter region of the AVP gene also contains a cAMP response element (CRE) site that is involved in gene expression regulation. Daily rhythms in the phosphorylation of the CRE binding protein (CREB) supports that these elements also contribute to circadian rhythmicity of the gene expression. CRE/CREB-mediated regulation of the AVP gene is activated through the cAMP activation of Ras signaling pathways, culminating in the MAP kinase phosphorylation of the CREB transcription factor.^[10]

Transcription of the AVP gene to produce AVP mRNA has daily rhythms, with mRNA levels peaking during the subjective day and reaching their lowest point in the subject night. This rhythm is regulated by the binding of circadian proteins to the E-box, along with transcriptional regulation of other elements, including the CRE in the promoter region.^[10]

Function

AVP is primarily known for its role as a mammalian circadian output.^[11]^[12] The most common product of AVP is vasopressin, which is a neurohypophysial hormone that is important in homeostatic mechanisms and processes, like cortical EEG rhythms. Its other products are neurophysin II and copeptin. AVP is produced in a specific type of neuron called magnocellular neurons (MCNs), which are located in the hypothalamus.^[12] In mammals, the AVP gene is also transcribed in the suprachiasmatic nucleus where its expression is under the control of the circadian TTFL.^[13] It is well established that the finished vasopressin product is transported from the cell body to the terminals in the posterior pituitary gland where it is released into the bloodstream as a result of environmental stressors like dehydration.^[14]

Gene Regulation

AVP gene regulation is controlled by the TTFL. In this system, per2 protein is transcribed and phosphorylated by the CK1E enzyme. Accumulation of this protein inhibits the transcription factors Clock and BMAL1, so that no additional per product is created.^[15] At the same time, per2 inhibits the transcription factors driving the AVP gene so that its expression and products are reduced.^[14] It can be noted that AVP expression is regulated by the TTFL in the SCN but not in the paraventricular nucleus of the hypothalamus (PVH) and supraoptic nucleus (SON).^[16]

Receptor Pathways

The transcription of the AVP gene commonly results in the binding of vasopressin to one of three vasopressin receptors: AVPR1A, AVPR1B, and AVPR2. When vasopressin binds to AVPR1A, a G-protein coupled receptor (GPCR), phospholipase C (PLC) becomes activated.^[17]^[18] This pathway typically involves regulating vasoconstriction. When vasopressin binds to AVPR1B, a GPCR, the phosphatidylinositol-calcium second messenger system is stimulated. AVPR1A and AVPR1B are GPCRs that stimulate PLC to promote the production of DAG which activates PKC and IP3 and stimulates calcium ion release from the ER. This signaling pathway is important in regulating homeostasis and the amount of water, glucose, and salts within the blood via ACTH release and storage.^[19] When vasopressin binds to AVPR2, another GPCR, adenylyl cyclase is stimulated. This second messenger pathway involves the regulation of ADH, or vasopressin, in the kidneys, which has an important diuretic purpose of retaining water and manipulating the concentrations of soluble toxic wastes and urea in urine.^[20]

AVP gene in rats

Within rats, the AVP gene is important for the regulation of various processes associated with the excretory system and smooth muscle cells. The AVP gene and arginine vasopressin are commonly colocalized with oxytocin because synaptic transmission of oxytocin regulates the expression of AVP mRNA.^[21]

In one study conducted by Greenwood and colleagues, researchers found that AVP gene expression in rats is regulated by the cAMP responsive element-binding protein-3 like-1 (CREB3L1). CREB3L1 is activated when it is cleaved and when the AVP gene is translocated from the Golgi to the nucleus.^[22] Additionally, CREB3L1 mRNA levels correspond with increased amounts of transcription of the AVP gene in the hypothalamus following a deficiency of sodium and as a consequence of diurnal rhythm in the SCN.^[22] Both full-length and constitutively active forms of CREB3L1 (CREB3L1CA) induce the expression of rat AVP promoter-luciferase reporter constructs whereas a dominant-negative mutant reduces expression. From this study, the researchers concluded that CREB3L1 is a regulator of AVP gene transcription in the hypothalamus and specifically within the PVH and SON.

Arginine vasopressin stimulates the process of phosphorylation of aquaporin 2 (AQP2) of renal tissue which contributes to the overall increased permeability of water in the collecting duct cells of the tissue. The phosphorylation of AQP2 leads to activation of the protein kinase A signaling pathway which amplifies the permeability of water by stimulating the rat equivalent of the urea transporter 1 protein.^[23]

Medical applications

Main Article: Vasopressin (medication)

The functions of vasopressin make it useful for a variety of important medical applications. Since it plays a role in the regulation of many physiological functions, like regulation of water and sodium excretion, blood volume, vasoconstriction, and response to stress, vasopressin can be helpful in the treatment of conditions related to these functions.^[24] These applications include treatment of nocturnal enuresis, diabetes insipidus, and hemophilia A.^[25] Additionally, it is used to treat some forms of shock including septic shock and vasodilatory shock. It is also used during surgery to decrease blood loss.^[26]

References

^ Albers, H. Elliott (January 2015). "Species, Sex and Individual Differences in the Vasotocin/Vasopressin System: Relationship to Neurochemical Signaling in the Social Behavior Neural Network". Frontiers in Neuroendocrinology. 36: 49–71. doi:10.1016/j.yfrne.2014.07.001. PMC 4317378. PMID 25102443.
^ Thomas, Ryckmans (2010). "Modulation of the vasopressin system for the treatment of CNS diseases". Current Opinion in Drug Discovery and Development. 13 (5): 538–547. PMID 20812145. Retrieved 5/6/2021. {{cite journal}}: Check date values in: |access-date= (help)
^ Oliver, G.; Schäfer, E. A. (1895-07-18). "On the Physiological Action of Extracts of Pituitary Body and certain other Glandular Organs: Preliminary Communication". The Journal of Physiology. 18 (3): 277–279. doi:10.1113/jphysiol.1895.sp000565. ISSN 0022-3751. PMC 1514634. PMID 16992253.
^ Kamm, Oliver; Aldrich, T. B.; Grote, I. W.; Rowe, L. W.; Bugbee, E. P. (1928-02-01). "The Active Principles of the Posterior Lobe of the Pituitary Gland.1 I. The Demonstration of the Presence of Two Active Principles. Ii. The Separation of the Two Principles and Their Concentration in the Form of Potent Solid Preparations". Journal of the American Chemical Society. 50 (2): 573–601. doi:10.1021/ja01389a050. ISSN 0002-7863.
^ Turner, R. A.; Pierce, J. G.; du VIGNEAUD, V. (July 1951). "The purification and the amino acid content of vasopressin preparations". The Journal of Biological Chemistry. 191 (1): 21–28. doi:10.1016/S0021-9258(18)50947-9. ISSN 0021-9258. PMID 14850440.
^ du Vigneaud, Vincent; Gish, Duane T.; Katsoyannis, Panayotis G. (1954-09-01). "A Synthetic Preparation Possessing Biological Properties Associated with Argininevasopressin". Journal of the American Chemical Society. 76 (18): 4751–4752. doi:10.1021/ja01647a089. ISSN 0002-7863.
^ Gainer, H.; Sarne, Y.; Brownstein, M. J. (1977-03-25). "Neurophysin biosynthesis: conversion of a putative precursor during axonal transport". Science. 195 (4284): 1354–1356. Bibcode:1977Sci...195.1354G. doi:10.1126/science.65791. ISSN 0036-8075. PMID 65791. S2CID 22281152.
^ Land, H.; Schütz, G.; Schmale, H.; Richter, D. (1982-01-28). "Nucleotide sequence of cloned cDNA encoding bovine arginine vasopressin-neurophysin II precursor". Nature. 295 (5847): 299–303. Bibcode:1982Natur.295..299L. doi:10.1038/295299a0. ISSN 0028-0836. PMID 6276766. S2CID 4340962.
^ ^a ^b Schmale, H; Heinsohn, S; Richter, D (1983). "Structural organization of the rat gene for the arginine vasopressin-neurophysin precursor". The EMBO Journal. 2 (5): 763–767. doi:10.1002/j.1460-2075.1983.tb01497.x. ISSN 0261-4189. PMC 555182. PMID 6315416.
^ ^a ^b ^c Arima, Hiroshi; House, Shirley B.; Gainer, Harold; Aguilera, Greti (November 2002). "Neuronal activity is required for the circadian rhythm of vasopressin gene transcription in the suprachiasmatic nucleus in vitro". Endocrinology. 143 (11): 4165–4171. doi:10.1210/en.2002-220393. ISSN 0013-7227. PMID 12399408.
^ ^a ^b Mieda, Michihiro (2019-02-25). "The Network Mechanism of the Central Circadian Pacemaker of the SCN: Do AVP Neurons Play a More Critical Role Than Expected?". Frontiers in Neuroscience. 13: 139. doi:10.3389/fnins.2019.00139. ISSN 1662-4548. PMC 6397828. PMID 30858797.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ ^a ^b Ingram, C.D.; Ciobanu, R.; Coculescu, I.L.; Tanasescu, R.; Coculescu, M.; Mihai, R. (1999-01-01). "Vasopressin neurotransmission and the control of circadian rhythms in the suprachiasmatic nucleus". Progress in Brain Research. 119: 351–364. doi:10.1016/S0079-6123(08)61580-0. ISBN 9780444500809. ISSN 0079-6123. PMID 10074799.
^ Antunes-Rodrigues, José; de Castro, Margaret; Elias, Lucila L. K.; Valença, Marcelo M.; McCann, Samuel M. (January 2004). "Neuroendocrine control of body fluid metabolism". Physiological Reviews. 84 (1): 169–208. doi:10.1152/physrev.00017.2003. ISSN 0031-9333. PMID 14715914.
^ ^a ^b Jin, X.; Shearman, L. P.; Weaver, D. R.; Zylka, M. J.; de Vries, G. J.; Reppert, S. M. (1999-01-08). "A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock". Cell. 96 (1): 57–68. doi:10.1016/s0092-8674(00)80959-9. ISSN 0092-8674. PMID 9989497. S2CID 6916996.
^ Dunlap, J. C. (1999-01-22). "Molecular bases for circadian clocks". Cell. 96 (2): 271–290. doi:10.1016/s0092-8674(00)80566-8. ISSN 0092-8674. PMID 9988221. S2CID 14991100.
^ "AVP arginine vasopressin [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-05-02.
^ Bourque, Charles W. (July 2008). "Central mechanisms of osmosensation and systemic osmoregulation". Nature Reviews. Neuroscience. 9 (7): 519–531. doi:10.1038/nrn2400. ISSN 1471-0048. PMID 18509340. S2CID 205504313.
^ Caldwell, Heather K.; Lee, Heon-Jin; Macbeth, Abbe H.; Young, W. Scott (January 2008). "Vasopressin: Behavioral Roles of an "Original" Neuropeptide". Progress in Neurobiology. 84 (1): 1–24. doi:10.1016/j.pneurobio.2007.10.007. ISSN 0301-0082. PMC 2292122. PMID 18053631.
^ Thibonnier, M.; Auzan, C.; Madhun, Z.; Wilkins, P.; Berti-Mattera, L.; Clauser, E. (1994-02-04). "Molecular cloning, sequencing, and functional expression of a cDNA encoding the human V1a vasopressin receptor". The Journal of Biological Chemistry. 269 (5): 3304–3310. doi:10.1016/S0021-9258(17)41863-1. ISSN 0021-9258. PMID 8106369.
^ Holmes, Cheryl L.; Landry, Donald W.; Granton, John T. (December 2003). "Science review: Vasopressin and the cardiovascular system part 1--receptor physiology". Critical Care (London, England). 7 (6): 427–434. doi:10.1186/cc2337. ISSN 1364-8535. PMC 374366. PMID 14624682.
^ Baldino, F.; O'Kane, T. M.; Fitzpatrick-McElligott, S.; Wolfson, B. (1988-08-19). "Coordinate hormonal and synaptic regulation of vasopressin messenger RNA". Science. 241 (4868): 978–981. Bibcode:1988Sci...241..978B. doi:10.1126/science.3406747. ISSN 0036-8075. PMID 3406747.
^ ^a ^b Greenwood, Mingkwan; Bordieri, Loredana; Greenwood, Michael P.; Rosso Melo, Mariana; Colombari, Debora S. A.; Colombari, Eduardo; Paton, Julian F. R.; Murphy, David (2014-03-12). "Transcription factor CREB3L1 regulates vasopressin gene expression in the rat hypothalamus". The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 34 (11): 3810–3820. doi:10.1523/JNEUROSCI.4343-13.2014. ISSN 1529-2401. PMC 3951688. PMID 24623760.
^ Nishimoto, G.; Zelenina, M.; Li, D.; Yasui, M.; Aperia, A.; Nielsen, S.; Nairn, A. C. (1999-02-XX). "Arginine vasopressin stimulates phosphorylation of aquaporin-2 in rat renal tissue". The American Journal of Physiology. 276 (2): F254–259. doi:10.1152/ajprenal.1999.276.2.F254. ISSN 0002-9513. PMID 9950956. {{cite journal}}: Check date values in: |date= (help)
^ Gassanov, Natig; Semmo, Nasser; Semmo, Mariam (2/17/2011). "Arginine vasopressin (AVP) and treatment with arginine vasopressin receptor antagonists (vaptans) in congestive heart failure, liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion (SIADH)". European Journal of Clinical Pharmacology. 67 (4): 333–346. doi:10.1007/s00228-011-1006-7. PMID 21327910. S2CID 1477146. Retrieved 2021-05-06. {{cite journal}}: Check date values in: |date= (help)
^ Agrawal, Amit; Singh, Vishal K.; Varma, Amit; Sharma, Rajesh (April 2012). "Therapeutic applications of vasopressin in pediatric patients". Indian Pediatrics. 49 (4): 297–305. doi:10.1007/s13312-012-0046-0. ISSN 0974-7559. PMID 22565074. S2CID 9836092.
^ Frishman, Gary (2009-02-XX). "Vasopressin: If Some Is Good, Is More Better?". Obstetrics & Gynecology. 113 (2 Part 2): 476–477. doi:10.1097/AOG.0b013e31819698bb. ISSN 0029-7844. PMID 19155925. {{cite journal}}: Check date values in: |date= (help)

[1] Albers, H. Elliott (January 2015). "Species, Sex and Individual Differences in the Vasotocin/Vasopressin System: Relationship to Neurochemical Signaling in the Social Behavior Neural Network". Frontiers in Neuroendocrinology. 36: 49–71. doi:10.1016/j.yfrne.2014.07.001. PMC 4317378. PMID 25102443.

[2] Thomas, Ryckmans (2010). "Modulation of the vasopressin system for the treatment of CNS diseases". Current Opinion in Drug Discovery and Development. 13 (5): 538–547. PMID 20812145. Retrieved 5/6/2021. {{cite journal}}: Check date values in: |access-date= (help)

[3] Oliver, G.; Schäfer, E. A. (1895-07-18). "On the Physiological Action of Extracts of Pituitary Body and certain other Glandular Organs: Preliminary Communication". The Journal of Physiology. 18 (3): 277–279. doi:10.1113/jphysiol.1895.sp000565. ISSN 0022-3751. PMC 1514634. PMID 16992253.

[4] Kamm, Oliver; Aldrich, T. B.; Grote, I. W.; Rowe, L. W.; Bugbee, E. P. (1928-02-01). "The Active Principles of the Posterior Lobe of the Pituitary Gland.1 I. The Demonstration of the Presence of Two Active Principles. Ii. The Separation of the Two Principles and Their Concentration in the Form of Potent Solid Preparations". Journal of the American Chemical Society. 50 (2): 573–601. doi:10.1021/ja01389a050. ISSN 0002-7863.

[5] Turner, R. A.; Pierce, J. G.; du VIGNEAUD, V. (July 1951). "The purification and the amino acid content of vasopressin preparations". The Journal of Biological Chemistry. 191 (1): 21–28. doi:10.1016/S0021-9258(18)50947-9. ISSN 0021-9258. PMID 14850440.

[6] u Vigneaud, Vincent; Gish, Duane T.; Katsoyannis, Panayotis G. (1954-09-01). "A Synthetic Preparation Possessing Biological Properties Associated with Argininevasopressin". Journal of the American Chemical Society. 76 (18): 4751–4752. doi:10.1021/ja01647a089. ISSN 0002-7863.

[7] Gainer, H.; Sarne, Y.; Brownstein, M. J. (1977-03-25). "Neurophysin biosynthesis: conversion of a putative precursor during axonal transport". Science. 195 (4284): 1354–1356. Bibcode:1977Sci...195.1354G. doi:10.1126/science.65791. ISSN 0036-8075. PMID 65791. S2CID 22281152.

[8] Land, H.; Schütz, G.; Schmale, H.; Richter, D. (1982-01-28). "Nucleotide sequence of cloned cDNA encoding bovine arginine vasopressin-neurophysin II precursor". Nature. 295 (5847): 299–303. Bibcode:1982Natur.295..299L. doi:10.1038/295299a0. ISSN 0028-0836. PMID 6276766. S2CID 4340962.

[:0-9] Schmale, H; Heinsohn, S; Richter, D (1983). "Structural organization of the rat gene for the arginine vasopressin-neurophysin precursor". The EMBO Journal. 2 (5): 763–767. doi:10.1002/j.1460-2075.1983.tb01497.x. ISSN 0261-4189. PMC 555182. PMID 6315416.

[:1-10] Arima, Hiroshi; House, Shirley B.; Gainer, Harold; Aguilera, Greti (November 2002). "Neuronal activity is required for the circadian rhythm of vasopressin gene transcription in the suprachiasmatic nucleus in vitro". Endocrinology. 143 (11): 4165–4171. doi:10.1210/en.2002-220393. ISSN 0013-7227. PMID 12399408.

[:2-11] Mieda, Michihiro (2019-02-25). "The Network Mechanism of the Central Circadian Pacemaker of the SCN: Do AVP Neurons Play a More Critical Role Than Expected?". Frontiers in Neuroscience. 13: 139. doi:10.3389/fnins.2019.00139. ISSN 1662-4548. PMC 6397828. PMID 30858797.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[:3-12] Ingram, C.D.; Ciobanu, R.; Coculescu, I.L.; Tanasescu, R.; Coculescu, M.; Mihai, R. (1999-01-01). "Vasopressin neurotransmission and the control of circadian rhythms in the suprachiasmatic nucleus". Progress in Brain Research. 119: 351–364. doi:10.1016/S0079-6123(08)61580-0. ISBN 9780444500809. ISSN 0079-6123. PMID 10074799.

[13] Antunes-Rodrigues, José; de Castro, Margaret; Elias, Lucila L. K.; Valença, Marcelo M.; McCann, Samuel M. (January 2004). "Neuroendocrine control of body fluid metabolism". Physiological Reviews. 84 (1): 169–208. doi:10.1152/physrev.00017.2003. ISSN 0031-9333. PMID 14715914.

[Jin_57–68-14] Jin, X.; Shearman, L. P.; Weaver, D. R.; Zylka, M. J.; de Vries, G. J.; Reppert, S. M. (1999-01-08). "A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock". Cell. 96 (1): 57–68. doi:10.1016/s0092-8674(00)80959-9. ISSN 0092-8674. PMID 9989497. S2CID 6916996.

[15] Dunlap, J. C. (1999-01-22). "Molecular bases for circadian clocks". Cell. 96 (2): 271–290. doi:10.1016/s0092-8674(00)80566-8. ISSN 0092-8674. PMID 9988221. S2CID 14991100.

[16] "AVP arginine vasopressin [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2021-05-02.

[17] Bourque, Charles W. (July 2008). "Central mechanisms of osmosensation and systemic osmoregulation". Nature Reviews. Neuroscience. 9 (7): 519–531. doi:10.1038/nrn2400. ISSN 1471-0048. PMID 18509340. S2CID 205504313.

[18] Caldwell, Heather K.; Lee, Heon-Jin; Macbeth, Abbe H.; Young, W. Scott (January 2008). "Vasopressin: Behavioral Roles of an "Original" Neuropeptide". Progress in Neurobiology. 84 (1): 1–24. doi:10.1016/j.pneurobio.2007.10.007. ISSN 0301-0082. PMC 2292122. PMID 18053631.

[19] Thibonnier, M.; Auzan, C.; Madhun, Z.; Wilkins, P.; Berti-Mattera, L.; Clauser, E. (1994-02-04). "Molecular cloning, sequencing, and functional expression of a cDNA encoding the human V1a vasopressin receptor". The Journal of Biological Chemistry. 269 (5): 3304–3310. doi:10.1016/S0021-9258(17)41863-1. ISSN 0021-9258. PMID 8106369.

[20] Holmes, Cheryl L.; Landry, Donald W.; Granton, John T. (December 2003). "Science review: Vasopressin and the cardiovascular system part 1--receptor physiology". Critical Care (London, England). 7 (6): 427–434. doi:10.1186/cc2337. ISSN 1364-8535. PMC 374366. PMID 14624682.

[21] Baldino, F.; O'Kane, T. M.; Fitzpatrick-McElligott, S.; Wolfson, B. (1988-08-19). "Coordinate hormonal and synaptic regulation of vasopressin messenger RNA". Science. 241 (4868): 978–981. Bibcode:1988Sci...241..978B. doi:10.1126/science.3406747. ISSN 0036-8075. PMID 3406747.

[:4-22] Greenwood, Mingkwan; Bordieri, Loredana; Greenwood, Michael P.; Rosso Melo, Mariana; Colombari, Debora S. A.; Colombari, Eduardo; Paton, Julian F. R.; Murphy, David (2014-03-12). "Transcription factor CREB3L1 regulates vasopressin gene expression in the rat hypothalamus". The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 34 (11): 3810–3820. doi:10.1523/JNEUROSCI.4343-13.2014. ISSN 1529-2401. PMC 3951688. PMID 24623760.

[23] Nishimoto, G.; Zelenina, M.; Li, D.; Yasui, M.; Aperia, A.; Nielsen, S.; Nairn, A. C. (1999-02-XX). "Arginine vasopressin stimulates phosphorylation of aquaporin-2 in rat renal tissue". The American Journal of Physiology. 276 (2): F254–259. doi:10.1152/ajprenal.1999.276.2.F254. ISSN 0002-9513. PMID 9950956. {{cite journal}}: Check date values in: |date= (help)

[24] Gassanov, Natig; Semmo, Nasser; Semmo, Mariam (2/17/2011). "Arginine vasopressin (AVP) and treatment with arginine vasopressin receptor antagonists (vaptans) in congestive heart failure, liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion (SIADH)". European Journal of Clinical Pharmacology. 67 (4): 333–346. doi:10.1007/s00228-011-1006-7. PMID 21327910. S2CID 1477146. Retrieved 2021-05-06. {{cite journal}}: Check date values in: |date= (help)

[25] Agrawal, Amit; Singh, Vishal K.; Varma, Amit; Sharma, Rajesh (April 2012). "Therapeutic applications of vasopressin in pediatric patients". Indian Pediatrics. 49 (4): 297–305. doi:10.1007/s13312-012-0046-0. ISSN 0974-7559. PMID 22565074. S2CID 9836092.

[26] Frishman, Gary (2009-02-XX). "Vasopressin: If Some Is Good, Is More Better?". Obstetrics & Gynecology. 113 (2 Part 2): 476–477. doi:10.1097/AOG.0b013e31819698bb. ISSN 0029-7844. PMID 19155925. {{cite journal}}: Check date values in: |date= (help)

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-'''Arginine Vasopressin (AVP) Gene''' is a gene whose product is [[Proteolysis|proteolytically cleaved]] to produce vasopressin (also known as antidiuretic hormone, [[Antidiuretic Hormone|ADH]]), [[neurophysin II]], and a glycoprotein called copeptin. AVP and other AVP-like peptides are found in mammals, as well as mollusks, arthropods, nematodes, and other invertebrate species.<ref>{{cite journal |last1=Albers |first1=H. Elliott |title=Species, Sex and Individual Differences in the Vasotocin/Vasopressin System: Relationship to Neurochemical Signaling in the Social Behavior Neural Network |journal=Frontiers in Neuroendocrinology |date=January 2015 |volume=36 |page=49-71 |doi=10.1016/j.yfrne.2014.07.001 |pmid=25102443 |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317378/#:~:text=The%20AVP%2FOT%20family%20of,Hasunuma%20and%20others%2C%202013 |access-date=May 6, 2021}}</ref> In humans, AVP is present on chromosome 20 and plays a role in homeostatic regulation. The products of AVP have many functions that include [[vasoconstriction]], regulating the balance of water in the body, and regulating responses to [[Stress (biology)|stress]].<ref>{{cite journal |last1=Thomas |first1=Ryckmans |title=Modulation of the vasopressin system for the treatment of CNS diseases |journal=Current Opinion in Drug Discovery and Development |date=2010 |volume=13 |issue=5 |page=538-547 |pmid=20812145 |url=https://pubmed.ncbi.nlm.nih.gov/20812145/ |access-date=5/6/2021}}</ref> Expression of AVP is regulated by the [[Transcription translation feedback loop|Transcription Translation Feedback Loop (TTFL)]], which is an important part of the [[Circadian clock|circadian system]] that controls the expression of clock genes. AVP has important implications in the medical field as its products have significant roles throughout body.
+'''Arginine Vasopressin (AVP) Gene''' is a gene whose product is [[Proteolysis|proteolytically cleaved]] to produce vasopressin (also known as antidiuretic hormone, [[Antidiuretic Hormone|ADH]]), [[neurophysin II]], and a glycoprotein called copeptin. AVP and other AVP-like peptides are found in mammals, as well as mollusks, arthropods, nematodes, and other invertebrate species.<ref>{{cite journal |last1=Albers |first1=H. Elliott |title=Species, Sex and Individual Differences in the Vasotocin/Vasopressin System: Relationship to Neurochemical Signaling in the Social Behavior Neural Network |journal=Frontiers in Neuroendocrinology |date=January 2015 |volume=36 |pages=49–71 |doi=10.1016/j.yfrne.2014.07.001 |pmid=25102443 |pmc=4317378 }}</ref> In humans, AVP is present on chromosome 20 and plays a role in homeostatic regulation. The products of AVP have many functions that include [[vasoconstriction]], regulating the balance of water in the body, and regulating responses to [[Stress (biology)|stress]].<ref>{{cite journal |last1=Thomas |first1=Ryckmans |title=Modulation of the vasopressin system for the treatment of CNS diseases |journal=Current Opinion in Drug Discovery and Development |date=2010 |volume=13 |issue=5 |pages=538–547 |pmid=20812145 |url=https://pubmed.ncbi.nlm.nih.gov/20812145/ |access-date=5/6/2021}}</ref> Expression of AVP is regulated by the [[Transcription translation feedback loop|Transcription Translation Feedback Loop (TTFL)]], which is an important part of the [[Circadian clock|circadian system]] that controls the expression of clock genes. AVP has important implications in the medical field as its products have significant roles throughout body.
 == Discovery ==
 === Vasopressin ===
-The discovery of the AVP gene first required the discovery of one of its key products: [[vasopressin]]. In 1895, [[George Oliver (physician)|G. Oliver]] and [[Edward Albert Sharpey-Schafer|E.A. Schäfer]] found that a substance released by the pituitary gland could elevate blood pressure. The researchers noted that intravenous injection of extracts from the [[pituitary gland]], thyroid gland, and spleen all influence blood pressure, however the effect from the pituitary had the most significant impact.<ref>{{Cite journal|last=Oliver|first=G.|last2=Schäfer|first2=E. A.|date=1895-07-18|title=On the Physiological Action of Extracts of Pituitary Body and certain other Glandular Organs: Preliminary Communication|url=https://pubmed.ncbi.nlm.nih.gov/16992253/|journal=The Journal of Physiology|volume=18|issue=3|pages=277–279|doi=10.1113/jphysiol.1895.sp000565|issn=0022-3751|pmc=1514634|pmid=16992253}}</ref> Almost thirty years later, Kamm and colleagues separated the components within the pituitary gland. Using a unique, five-step separation technique, Kamm revealed one substance associated with uterine contractions – [[oxytocin]] – and another substance associated with blood pressure – vasopressin.<ref>{{Cite journal|last=Kamm|first=Oliver|last2=Aldrich|first2=T. B.|last3=Grote|first3=I. W.|last4=Rowe|first4=L. W.|last5=Bugbee|first5=E. P.|date=1928-02-01|title=THE ACTIVE PRINCIPLES OF THE POSTERIOR LOBE OF THE PITUITARY GLAND.1 I. THE DEMONSTRATION OF THE PRESENCE OF TWO ACTIVE PRINCIPLES. II. THE SEPARATION OF THE TWO PRINCIPLES AND THEIR CONCENTRATION IN THE FORM OF POTENT SOLID PREPARATIONS|url=https://doi.org/10.1021/ja01389a050|journal=Journal of the American Chemical Society|volume=50|issue=2|pages=573–601|doi=10.1021/ja01389a050|issn=0002-7863}}</ref>
+The discovery of the AVP gene first required the discovery of one of its key products: [[vasopressin]]. In 1895, [[George Oliver (physician)|G. Oliver]] and [[Edward Albert Sharpey-Schafer|E.A. Schäfer]] found that a substance released by the pituitary gland could elevate blood pressure. The researchers noted that intravenous injection of extracts from the [[pituitary gland]], thyroid gland, and spleen all influence blood pressure, however the effect from the pituitary had the most significant impact.<ref>{{Cite journal|last1=Oliver|first1=G.|last2=Schäfer|first2=E. A.|date=1895-07-18|title=On the Physiological Action of Extracts of Pituitary Body and certain other Glandular Organs: Preliminary Communication|url=https://pubmed.ncbi.nlm.nih.gov/16992253/|journal=The Journal of Physiology|volume=18|issue=3|pages=277–279|doi=10.1113/jphysiol.1895.sp000565|issn=0022-3751|pmc=1514634|pmid=16992253}}</ref> Almost thirty years later, Kamm and colleagues separated the components within the pituitary gland. Using a unique, five-step separation technique, Kamm revealed one substance associated with uterine contractions – [[oxytocin]] – and another substance associated with blood pressure – vasopressin.<ref>{{Cite journal|last1=Kamm|first1=Oliver|last2=Aldrich|first2=T. B.|last3=Grote|first3=I. W.|last4=Rowe|first4=L. W.|last5=Bugbee|first5=E. P.|title=The Active Principles of the Posterior Lobe of the Pituitary Gland.1 I. The Demonstration of the Presence of Two Active Principles. Ii. The Separation of the Two Principles and Their Concentration in the Form of Potent Solid Preparations|date=1928-02-01|url=https://doi.org/10.1021/ja01389a050|journal=Journal of the American Chemical Society|volume=50|issue=2|pages=573–601|doi=10.1021/ja01389a050|issn=0002-7863}}</ref>
-Once the discovery and separation of vasopressin occurred, subsequent research on the product's structure, function, and mode of generation could take place. In 1951, Turner and colleagues uncovered the amino acid sequence behind the hormone. The amino acid structure was composed of eight amino acids, including phenylalanine, tyrosine, proline, glutamic acid, aspartic acid, glycine, arginine, and cystine. The structure was also found to include ammonia.<ref>{{Cite journal|last=Turner|first=R. A.|last2=Pierce|first2=J. G.|last3=du VIGNEAUD|first3=V.|date=July 1951|title=The purification and the amino acid content of vasopressin preparations|url=https://pubmed.ncbi.nlm.nih.gov/14850440/|journal=The Journal of Biological Chemistry|volume=191|issue=1|pages=21–28|issn=0021-9258|pmid=14850440}}</ref> Following this discovery, [[Vincent du Vigneaud]] was able to synthesize a synthetic form of vasopressin in a laboratory setting. Du Vigneaud specifically noted that his final product had the same activity and composition ratios as that of naturally occurring vasopressin.<ref>{{Cite journal|last=du Vigneaud|first=Vincent|last2=Gish|first2=Duane T.|last3=Katsoyannis|first3=Panayotis G.|date=1954-09-01|title=A SYNTHETIC PREPARATION POSSESSING BIOLOGICAL PROPERTIES ASSOCIATED WITH ARGININEVASOPRESSIN|url=https://doi.org/10.1021/ja01647a089|journal=Journal of the American Chemical Society|volume=76|issue=18|pages=4751–4752|doi=10.1021/ja01647a089|issn=0002-7863}}</ref>
+Once the discovery and separation of vasopressin occurred, subsequent research on the product's structure, function, and mode of generation could take place. In 1951, Turner and colleagues uncovered the amino acid sequence behind the hormone. The amino acid structure was composed of eight amino acids, including phenylalanine, tyrosine, proline, glutamic acid, aspartic acid, glycine, arginine, and cystine. The structure was also found to include ammonia.<ref>{{Cite journal|last1=Turner|first1=R. A.|last2=Pierce|first2=J. G.|last3=du VIGNEAUD|first3=V.|date=July 1951|title=The purification and the amino acid content of vasopressin preparations|url=https://pubmed.ncbi.nlm.nih.gov/14850440/|journal=The Journal of Biological Chemistry|volume=191|issue=1|pages=21–28|doi=10.1016/S0021-9258(18)50947-9|issn=0021-9258|pmid=14850440}}</ref> Following this discovery, [[Vincent du Vigneaud]] was able to synthesize a synthetic form of vasopressin in a laboratory setting. Du Vigneaud specifically noted that his final product had the same activity and composition ratios as that of naturally occurring vasopressin.<ref>{{Cite journal|last1=du Vigneaud|first1=Vincent|last2=Gish|first2=Duane T.|last3=Katsoyannis|first3=Panayotis G.|title=A Synthetic Preparation Possessing Biological Properties Associated with Argininevasopressin|date=1954-09-01|url=https://doi.org/10.1021/ja01647a089|journal=Journal of the American Chemical Society|volume=76|issue=18|pages=4751–4752|doi=10.1021/ja01647a089|issn=0002-7863}}</ref>
 === AVP gene ===
-The work on vasopressin ultimately allowed researchers to work backwards and identify the gene responsible for this product's generation. This final stage of research began when Gainer and colleagues found a precursor protein to vasopressin in 1977.<ref>{{Cite journal|last=Gainer|first=H.|last2=Sarne|first2=Y.|last3=Brownstein|first3=M. J.|date=1977-03-25|title=Neurophysin biosynthesis: conversion of a putative precursor during axonal transport|url=https://pubmed.ncbi.nlm.nih.gov/65791/|journal=Science|volume=195|issue=4284|pages=1354–1356|doi=10.1126/science.65791|issn=0036-8075|pmid=65791}}</ref> The structure of the protein was subsequently discovered by Land in 1982. By sequencing complementary DNA strands that encoded for the hormone's mRNA, Land outlined the amino acid sequence of the precursor protein.<ref>{{Cite journal|last=Land|first=H.|last2=Schütz|first2=G.|last3=Schmale|first3=H.|last4=Richter|first4=D.|date=1982-01-28|title=Nucleotide sequence of cloned cDNA encoding bovine arginine vasopressin-neurophysin II precursor|url=https://pubmed.ncbi.nlm.nih.gov/6276766/|journal=Nature|volume=295|issue=5847|pages=299–303|doi=10.1038/295299a0|issn=0028-0836|pmid=6276766}}</ref> Finally, one year later, Schmale, Heinsohn, and Richter isolated the AVP precursor gene in rats from their genomic library. The researchers used [[restriction map]]ping and nucleotide sequence analysis to uncover the gene's three distinct exons and the products (vasopressin, neurophysin, and glycoprotein) that each was responsible for.<ref name=":0">{{Cite journal|last=Schmale|first=H|last2=Heinsohn|first2=S|last3=Richter|first3=D|date=1983|title=Structural organization of the rat gene for the arginine vasopressin-neurophysin precursor.|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC555182/|journal=The EMBO Journal|volume=2|issue=5|pages=763–767|issn=0261-4189|pmid=6315416}}</ref>
+The work on vasopressin ultimately allowed researchers to work backwards and identify the gene responsible for this product's generation. This final stage of research began when Gainer and colleagues found a precursor protein to vasopressin in 1977.<ref>{{Cite journal|last1=Gainer|first1=H.|last2=Sarne|first2=Y.|last3=Brownstein|first3=M. J.|date=1977-03-25|title=Neurophysin biosynthesis: conversion of a putative precursor during axonal transport|url=https://pubmed.ncbi.nlm.nih.gov/65791/|journal=Science|volume=195|issue=4284|pages=1354–1356|doi=10.1126/science.65791|issn=0036-8075|pmid=65791|bibcode=1977Sci...195.1354G|s2cid=22281152}}</ref> The structure of the protein was subsequently discovered by Land in 1982. By sequencing complementary DNA strands that encoded for the hormone's mRNA, Land outlined the amino acid sequence of the precursor protein.<ref>{{Cite journal|last1=Land|first1=H.|last2=Schütz|first2=G.|last3=Schmale|first3=H.|last4=Richter|first4=D.|date=1982-01-28|title=Nucleotide sequence of cloned cDNA encoding bovine arginine vasopressin-neurophysin II precursor|url=https://pubmed.ncbi.nlm.nih.gov/6276766/|journal=Nature|volume=295|issue=5847|pages=299–303|doi=10.1038/295299a0|issn=0028-0836|pmid=6276766|bibcode=1982Natur.295..299L|s2cid=4340962}}</ref> Finally, one year later, Schmale, Heinsohn, and Richter isolated the AVP precursor gene in rats from their genomic library. The researchers used [[restriction map]]ping and nucleotide sequence analysis to uncover the gene's three distinct exons and the products (vasopressin, neurophysin, and glycoprotein) that each was responsible for.<ref name=":0">{{Cite journal|last1=Schmale|first1=H|last2=Heinsohn|first2=S|last3=Richter|first3=D|date=1983|title=Structural organization of the rat gene for the arginine vasopressin-neurophysin precursor.|journal=The EMBO Journal|volume=2|issue=5|pages=763–767|doi=10.1002/j.1460-2075.1983.tb01497.x|issn=0261-4189|pmid=6315416|pmc=555182}}</ref>
 == Structure ==
@@ Line 16: / Line 16: @@
 === Promoter region ===
-The AVP gene promoter region consists of an [[E-box|E-box element]] located 150 residues upstreams of the transcription start site, which binds mammalian clock proteins [[CLK1|CLOCK]] and [[BMAL1]] involved in generating circadian rhythms in the [[Suprachiasmatic nucleus|suprachiasmatic nucleus (SCN)]].<ref name=":1">{{Cite journal|last=Arima|first=Hiroshi|last2=House|first2=Shirley B.|last3=Gainer|first3=Harold|last4=Aguilera|first4=Greti|date=November 2002|title=Neuronal activity is required for the circadian rhythm of vasopressin gene transcription in the suprachiasmatic nucleus in vitro|url=https://pubmed.ncbi.nlm.nih.gov/12399408/|journal=Endocrinology|volume=143|issue=11|pages=4165–4171|doi=10.1210/en.2002-220393|issn=0013-7227|pmid=12399408|doi-access=free}}</ref> BMAL1 and CLOCK gene knockouts in the SCN (Bmal-/- and clk-/-) eliminate rhythmicity in AVP mRNA expression, confirming that binding of the protein heterodimers to the E-box element is necessary for the intrinsic circadian pattern of the AVP gene.<ref name=":2">{{Cite journal|last=Mieda|first=Michihiro|date=2019-02-25|title=The Network Mechanism of the Central Circadian Pacemaker of the SCN: Do AVP Neurons Play a More Critical Role Than Expected?|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397828/|journal=Frontiers in Neuroscience|volume=13|doi=10.3389/fnins.2019.00139|issn=1662-4548|pmc=6397828|pmid=30858797}}</ref> In addition to the E-box element, the promoter region of the AVP gene also contains a [[CAMP response element|cAMP response element (CRE) site]] that is involved in gene expression regulation. Daily rhythms in the phosphorylation of the [[CREB-binding protein|CRE binding protein (CREB)]] supports that these elements also contribute to circadian rhythmicity of the gene expression. CRE/CREB-mediated regulation of the AVP gene is activated through the cAMP activation of Ras signaling pathways, culminating in the MAP kinase phosphorylation of the CREB transcription factor.<ref name=":1" />
+The AVP gene promoter region consists of an [[E-box|E-box element]] located 150 residues upstreams of the transcription start site, which binds mammalian clock proteins [[CLK1|CLOCK]] and [[BMAL1]] involved in generating circadian rhythms in the [[Suprachiasmatic nucleus|suprachiasmatic nucleus (SCN)]].<ref name=":1">{{Cite journal|last1=Arima|first1=Hiroshi|last2=House|first2=Shirley B.|last3=Gainer|first3=Harold|last4=Aguilera|first4=Greti|date=November 2002|title=Neuronal activity is required for the circadian rhythm of vasopressin gene transcription in the suprachiasmatic nucleus in vitro|url=https://pubmed.ncbi.nlm.nih.gov/12399408/|journal=Endocrinology|volume=143|issue=11|pages=4165–4171|doi=10.1210/en.2002-220393|issn=0013-7227|pmid=12399408|doi-access=free}}</ref> BMAL1 and CLOCK gene knockouts in the SCN (Bmal-/- and clk-/-) eliminate rhythmicity in AVP mRNA expression, confirming that binding of the protein heterodimers to the E-box element is necessary for the intrinsic circadian pattern of the AVP gene.<ref name=":2">{{Cite journal|last=Mieda|first=Michihiro|date=2019-02-25|title=The Network Mechanism of the Central Circadian Pacemaker of the SCN: Do AVP Neurons Play a More Critical Role Than Expected?|journal=Frontiers in Neuroscience|volume=13|page=139|doi=10.3389/fnins.2019.00139|issn=1662-4548|pmc=6397828|pmid=30858797}}</ref> In addition to the E-box element, the promoter region of the AVP gene also contains a [[CAMP response element|cAMP response element (CRE) site]] that is involved in gene expression regulation. Daily rhythms in the phosphorylation of the [[CREB-binding protein|CRE binding protein (CREB)]] supports that these elements also contribute to circadian rhythmicity of the gene expression. CRE/CREB-mediated regulation of the AVP gene is activated through the cAMP activation of Ras signaling pathways, culminating in the MAP kinase phosphorylation of the CREB transcription factor.<ref name=":1" />
 Transcription of the AVP gene to produce AVP mRNA has daily rhythms, with mRNA levels peaking during the subjective day and reaching their lowest point in the subject night. This rhythm is regulated by the binding of circadian proteins to the E-box, along with transcriptional regulation of other elements, including the CRE in the promoter region.<ref name=":1" />
 == Function ==
-AVP is primarily known for its role as a mammalian circadian output.<ref name=":2" /><ref name=":3">{{Cite journal|date=1999-01-01|title=Vasopressin neurotransmission and the control of circadian rhythms in the suprachiasmatic nucleus|url=https://www.sciencedirect.com/science/article/pii/S0079612308615800|journal=Progress in Brain Research|language=en|volume=119|pages=351–364|doi=10.1016/S0079-6123(08)61580-0|issn=0079-6123}}</ref> The most common product of AVP is vasopressin, which is a [[neurohypophysial hormone]] that is important in homeostatic mechanisms and processes, like [[cortical]] [[Electroencephalography|EEG]] rhythms. Its other products are neurophysin II and copeptin. AVP is produced in a specific type of neuron called [[Magnocellular neurosecretory cell|magnocellular neurons]] (MCNs), which are located in the [[hypothalamus]].<ref name=":3" /> In mammals, the AVP gene is also transcribed in the suprachiasmatic nucleus where its expression is under the control of the circadian TTFL.<ref>{{Cite journal|last=Antunes-Rodrigues|first=José|last2=de Castro|first2=Margaret|last3=Elias|first3=Lucila L. K.|last4=Valença|first4=Marcelo M.|last5=McCann|first5=Samuel M.|date=January 2004|title=Neuroendocrine control of body fluid metabolism|url=https://pubmed.ncbi.nlm.nih.gov/14715914/|journal=Physiological Reviews|volume=84|issue=1|pages=169–208|doi=10.1152/physrev.00017.2003|issn=0031-9333|pmid=14715914}}</ref> It is well established that the finished vasopressin product is transported from the cell body to the terminals in the posterior pituitary gland where it is released into the bloodstream as a result of environmental stressors like dehydration.<ref name="Jin 57–68">{{Cite journal|last=Jin|first=X.|last2=Shearman|first2=L. P.|last3=Weaver|first3=D. R.|last4=Zylka|first4=M. J.|last5=de Vries|first5=G. J.|last6=Reppert|first6=S. M.|date=1999-01-08|title=A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock|url=https://pubmed.ncbi.nlm.nih.gov/9989497/|journal=Cell|volume=96|issue=1|pages=57–68|doi=10.1016/s0092-8674(00)80959-9|issn=0092-8674|pmid=9989497}}</ref>
+AVP is primarily known for its role as a mammalian circadian output.<ref name=":2" /><ref name=":3">{{Cite journal|date=1999-01-01|title=Vasopressin neurotransmission and the control of circadian rhythms in the suprachiasmatic nucleus|url=https://www.sciencedirect.com/science/article/pii/S0079612308615800|journal=Progress in Brain Research|language=en|volume=119|pages=351–364|doi=10.1016/S0079-6123(08)61580-0|issn=0079-6123|last1=Ingram|first1=C.D.|last2=Ciobanu|first2=R.|last3=Coculescu|first3=I.L.|last4=Tanasescu|first4=R.|last5=Coculescu|first5=M.|last6=Mihai|first6=R.|pmid=10074799|isbn=9780444500809}}</ref> The most common product of AVP is vasopressin, which is a [[neurohypophysial hormone]] that is important in homeostatic mechanisms and processes, like [[cortical]] [[Electroencephalography|EEG]] rhythms. Its other products are neurophysin II and copeptin. AVP is produced in a specific type of neuron called [[Magnocellular neurosecretory cell|magnocellular neurons]] (MCNs), which are located in the [[hypothalamus]].<ref name=":3" /> In mammals, the AVP gene is also transcribed in the suprachiasmatic nucleus where its expression is under the control of the circadian TTFL.<ref>{{Cite journal|last1=Antunes-Rodrigues|first1=José|last2=de Castro|first2=Margaret|last3=Elias|first3=Lucila L. K.|last4=Valença|first4=Marcelo M.|last5=McCann|first5=Samuel M.|date=January 2004|title=Neuroendocrine control of body fluid metabolism|url=https://pubmed.ncbi.nlm.nih.gov/14715914/|journal=Physiological Reviews|volume=84|issue=1|pages=169–208|doi=10.1152/physrev.00017.2003|issn=0031-9333|pmid=14715914}}</ref> It is well established that the finished vasopressin product is transported from the cell body to the terminals in the posterior pituitary gland where it is released into the bloodstream as a result of environmental stressors like dehydration.<ref name="Jin 57–68">{{Cite journal|last1=Jin|first1=X.|last2=Shearman|first2=L. P.|last3=Weaver|first3=D. R.|last4=Zylka|first4=M. J.|last5=de Vries|first5=G. J.|last6=Reppert|first6=S. M.|date=1999-01-08|title=A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock|url=https://pubmed.ncbi.nlm.nih.gov/9989497/|journal=Cell|volume=96|issue=1|pages=57–68|doi=10.1016/s0092-8674(00)80959-9|issn=0092-8674|pmid=9989497|s2cid=6916996}}</ref>
 === Gene Regulation ===
-AVP gene regulation is controlled by the TTFL. In this system, [[PER2|per2]] protein is transcribed and phosphorylated by the [[Casein kinase 1 isoform epsilon|CK1E]] enzyme. Accumulation of this protein inhibits the transcription factors [[CLOCK|Clock]] and [[BMAL1]], so that no additional per product is created.<ref>{{Cite journal|last=Dunlap|first=J. C.|date=1999-01-22|title=Molecular bases for circadian clocks|url=https://pubmed.ncbi.nlm.nih.gov/9988221/|journal=Cell|volume=96|issue=2|pages=271–290|doi=10.1016/s0092-8674(00)80566-8|issn=0092-8674|pmid=9988221}}</ref> At the same time, per2 inhibits the transcription factors driving the AVP gene so that its expression and products are reduced.<ref name="Jin 57–68"/> It can be noted that AVP expression is regulated by the TTFL in the SCN but not in the [[Paraventricular nucleus of hypothalamus|paraventricular nucleus of the hypothalamus (PVH)]] and [[Supraoptic nucleus|supraoptic nucleus (SON)]].<ref>{{Cite web|title=AVP arginine vasopressin [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=551|access-date=2021-05-02|website=www.ncbi.nlm.nih.gov|language=en}}</ref>
+AVP gene regulation is controlled by the TTFL. In this system, [[PER2|per2]] protein is transcribed and phosphorylated by the [[Casein kinase 1 isoform epsilon|CK1E]] enzyme. Accumulation of this protein inhibits the transcription factors [[CLOCK|Clock]] and [[BMAL1]], so that no additional per product is created.<ref>{{Cite journal|last=Dunlap|first=J. C.|date=1999-01-22|title=Molecular bases for circadian clocks|url=https://pubmed.ncbi.nlm.nih.gov/9988221/|journal=Cell|volume=96|issue=2|pages=271–290|doi=10.1016/s0092-8674(00)80566-8|issn=0092-8674|pmid=9988221|s2cid=14991100}}</ref> At the same time, per2 inhibits the transcription factors driving the AVP gene so that its expression and products are reduced.<ref name="Jin 57–68"/> It can be noted that AVP expression is regulated by the TTFL in the SCN but not in the [[Paraventricular nucleus of hypothalamus|paraventricular nucleus of the hypothalamus (PVH)]] and [[Supraoptic nucleus|supraoptic nucleus (SON)]].<ref>{{Cite web|title=AVP arginine vasopressin [Homo sapiens (human)] - Gene - NCBI|url=https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=551|access-date=2021-05-02|website=www.ncbi.nlm.nih.gov|language=en}}</ref>
 === Receptor Pathways ===
-The transcription of the AVP gene commonly results in the binding of vasopressin to one of three vasopressin receptors: [[Vasopressin receptor 1A|AVPR1A]], [[Vasopressin receptor 1B|AVPR1B]], and [[Vasopressin receptor 2|AVPR2]]. When vasopressin binds to AVPR1A, a [[G protein-coupled receptor|G-protein coupled receptor (GPCR)]], [[phospholipase C|phospholipase C (PLC)]] becomes activated.<ref>{{Cite journal|last=Bourque|first=Charles W.|date=July 2008|title=Central mechanisms of osmosensation and systemic osmoregulation|url=https://pubmed.ncbi.nlm.nih.gov/18509340/|journal=Nature Reviews. Neuroscience|volume=9|issue=7|pages=519–531|doi=10.1038/nrn2400|issn=1471-0048|pmid=18509340}}</ref><ref>{{Cite journal|last=Caldwell|first=Heather K.|last2=Lee|first2=Heon-Jin|last3=Macbeth|first3=Abbe H.|last4=Young|first4=W. Scott|date=January 2008|title=Vasopressin: Behavioral Roles of an "Original" Neuropeptide|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2292122/|journal=Progress in neurobiology|volume=84|issue=1|pages=1–24|doi=10.1016/j.pneurobio.2007.10.007|issn=0301-0082|pmc=2292122|pmid=18053631}}</ref> This pathway typically involves regulating vasoconstriction. When vasopressin binds to AVPR1B, a GPCR, the phosphatidylinositol-calcium second messenger system is stimulated. AVPR1A and AVPR1B are GPCRs that stimulate PLC to promote the production of [[Diglyceride|DAG]] which activates PKC and [[Inositol trisphosphate|IP3]] and stimulates [[calcium ion]] release from the [[Endoplasmic reticulum|ER]]. This [[Ip3 dag pathway|signaling pathway]] is important in regulating homeostasis and the amount of water, glucose, and salts within the blood via [[Adrenocorticotropic hormone|ACTH]] release and storage.<ref>{{Cite journal|last=Thibonnier|first=M.|last2=Auzan|first2=C.|last3=Madhun|first3=Z.|last4=Wilkins|first4=P.|last5=Berti-Mattera|first5=L.|last6=Clauser|first6=E.|date=1994-02-04|title=Molecular cloning, sequencing, and functional expression of a cDNA encoding the human V1a vasopressin receptor|url=https://pubmed.ncbi.nlm.nih.gov/8106369/|journal=The Journal of Biological Chemistry|volume=269|issue=5|pages=3304–3310|issn=0021-9258|pmid=8106369}}</ref> When vasopressin binds to AVPR2, another GPCR, [[adenylyl cyclase]] is stimulated. This second messenger pathway involves the regulation of ADH, or vasopressin, in the kidneys, which has an important diuretic purpose of retaining water and manipulating the concentrations of soluble toxic wastes and urea in urine.<ref>{{Cite journal|last=Holmes|first=Cheryl L.|last2=Landry|first2=Donald W.|last3=Granton|first3=John T.|date=December 2003|title=Science review: Vasopressin and the cardiovascular system part 1--receptor physiology|url=https://pubmed.ncbi.nlm.nih.gov/14624682/|journal=Critical Care (London, England)|volume=7|issue=6|pages=427–434|doi=10.1186/cc2337|issn=1364-8535|pmid=14624682|doi-access=free}}</ref>
+The transcription of the AVP gene commonly results in the binding of vasopressin to one of three vasopressin receptors: [[Vasopressin receptor 1A|AVPR1A]], [[Vasopressin receptor 1B|AVPR1B]], and [[Vasopressin receptor 2|AVPR2]]. When vasopressin binds to AVPR1A, a [[G protein-coupled receptor|G-protein coupled receptor (GPCR)]], [[phospholipase C|phospholipase C (PLC)]] becomes activated.<ref>{{Cite journal|last=Bourque|first=Charles W.|date=July 2008|title=Central mechanisms of osmosensation and systemic osmoregulation|url=https://pubmed.ncbi.nlm.nih.gov/18509340/|journal=Nature Reviews. Neuroscience|volume=9|issue=7|pages=519–531|doi=10.1038/nrn2400|issn=1471-0048|pmid=18509340|s2cid=205504313}}</ref><ref>{{Cite journal|last1=Caldwell|first1=Heather K.|last2=Lee|first2=Heon-Jin|last3=Macbeth|first3=Abbe H.|last4=Young|first4=W. Scott|date=January 2008|title=Vasopressin: Behavioral Roles of an "Original" Neuropeptide|journal=Progress in Neurobiology|volume=84|issue=1|pages=1–24|doi=10.1016/j.pneurobio.2007.10.007|issn=0301-0082|pmc=2292122|pmid=18053631}}</ref> This pathway typically involves regulating vasoconstriction. When vasopressin binds to AVPR1B, a GPCR, the phosphatidylinositol-calcium second messenger system is stimulated. AVPR1A and AVPR1B are GPCRs that stimulate PLC to promote the production of [[Diglyceride|DAG]] which activates PKC and [[Inositol trisphosphate|IP3]] and stimulates [[calcium ion]] release from the [[Endoplasmic reticulum|ER]]. This [[Ip3 dag pathway|signaling pathway]] is important in regulating homeostasis and the amount of water, glucose, and salts within the blood via [[Adrenocorticotropic hormone|ACTH]] release and storage.<ref>{{Cite journal|last1=Thibonnier|first1=M.|last2=Auzan|first2=C.|last3=Madhun|first3=Z.|last4=Wilkins|first4=P.|last5=Berti-Mattera|first5=L.|last6=Clauser|first6=E.|date=1994-02-04|title=Molecular cloning, sequencing, and functional expression of a cDNA encoding the human V1a vasopressin receptor|url=https://pubmed.ncbi.nlm.nih.gov/8106369/|journal=The Journal of Biological Chemistry|volume=269|issue=5|pages=3304–3310|doi=10.1016/S0021-9258(17)41863-1|issn=0021-9258|pmid=8106369}}</ref> When vasopressin binds to AVPR2, another GPCR, [[adenylyl cyclase]] is stimulated. This second messenger pathway involves the regulation of ADH, or vasopressin, in the kidneys, which has an important diuretic purpose of retaining water and manipulating the concentrations of soluble toxic wastes and urea in urine.<ref>{{Cite journal|last1=Holmes|first1=Cheryl L.|last2=Landry|first2=Donald W.|last3=Granton|first3=John T.|date=December 2003|title=Science review: Vasopressin and the cardiovascular system part 1--receptor physiology|url=https://pubmed.ncbi.nlm.nih.gov/14624682/|journal=Critical Care (London, England)|volume=7|issue=6|pages=427–434|doi=10.1186/cc2337|issn=1364-8535|pmid=14624682|pmc=374366|doi-access=free}}</ref>
 === AVP gene in rats ===
-Within rats, the AVP gene is important for the regulation of various processes associated with the excretory system and smooth muscle cells. The AVP gene and arginine vasopressin are commonly [[Colocalization|colocalized]] with [[oxytocin]] because synaptic transmission of oxytocin regulates the expression of AVP mRNA.<ref>{{Cite journal|last=Baldino|first=F.|last2=O'Kane|first2=T. M.|last3=Fitzpatrick-McElligott|first3=S.|last4=Wolfson|first4=B.|date=1988-08-19|title=Coordinate hormonal and synaptic regulation of vasopressin messenger RNA|url=https://pubmed.ncbi.nlm.nih.gov/3406747/|journal=Science|volume=241|issue=4868|pages=978–981|doi=10.1126/science.3406747|issn=0036-8075|pmid=3406747}}</ref>
+Within rats, the AVP gene is important for the regulation of various processes associated with the excretory system and smooth muscle cells. The AVP gene and arginine vasopressin are commonly [[Colocalization|colocalized]] with [[oxytocin]] because synaptic transmission of oxytocin regulates the expression of AVP mRNA.<ref>{{Cite journal|last1=Baldino|first1=F.|last2=O'Kane|first2=T. M.|last3=Fitzpatrick-McElligott|first3=S.|last4=Wolfson|first4=B.|date=1988-08-19|title=Coordinate hormonal and synaptic regulation of vasopressin messenger RNA|url=https://pubmed.ncbi.nlm.nih.gov/3406747/|journal=Science|volume=241|issue=4868|pages=978–981|doi=10.1126/science.3406747|issn=0036-8075|pmid=3406747|bibcode=1988Sci...241..978B}}</ref>
-In one study conducted by Greenwood and colleagues, researchers found that AVP gene expression in rats is regulated by the [[CREB3L1|cAMP responsive element-binding protein-3 like-1 (CREB3L1)]].  CREB3L1 is activated when it is cleaved and when the AVP gene is translocated from the Golgi to the nucleus.<ref name=":4">{{Cite journal|last=Greenwood|first=Mingkwan|last2=Bordieri|first2=Loredana|last3=Greenwood|first3=Michael P.|last4=Rosso Melo|first4=Mariana|last5=Colombari|first5=Debora S. A.|last6=Colombari|first6=Eduardo|last7=Paton|first7=Julian F. R.|last8=Murphy|first8=David|date=2014-03-12|title=Transcription factor CREB3L1 regulates vasopressin gene expression in the rat hypothalamus|url=https://pubmed.ncbi.nlm.nih.gov/24623760/|journal=The Journal of Neuroscience: The Official Journal of the Society for Neuroscience|volume=34|issue=11|pages=3810–3820|doi=10.1523/JNEUROSCI.4343-13.2014|issn=1529-2401|pmc=3951688|pmid=24623760}}</ref> Additionally, CREB3L1 mRNA levels correspond with increased amounts of transcription of the AVP gene in the hypothalamus following a deficiency of sodium and as a consequence of diurnal rhythm in the SCN.<ref name=":4" /> Both full-length and constitutively active forms of CREB3L1 (CREB3L1CA) induce the expression of rat AVP promoter-luciferase reporter constructs whereas a dominant-negative mutant reduces expression. From this study, the researchers concluded that CREB3L1 is a regulator of AVP gene transcription in the hypothalamus and specifically within the PVH and SON.
+In one study conducted by Greenwood and colleagues, researchers found that AVP gene expression in rats is regulated by the [[CREB3L1|cAMP responsive element-binding protein-3 like-1 (CREB3L1)]].  CREB3L1 is activated when it is cleaved and when the AVP gene is translocated from the Golgi to the nucleus.<ref name=":4">{{Cite journal|last1=Greenwood|first1=Mingkwan|last2=Bordieri|first2=Loredana|last3=Greenwood|first3=Michael P.|last4=Rosso Melo|first4=Mariana|last5=Colombari|first5=Debora S. A.|last6=Colombari|first6=Eduardo|last7=Paton|first7=Julian F. R.|last8=Murphy|first8=David|date=2014-03-12|title=Transcription factor CREB3L1 regulates vasopressin gene expression in the rat hypothalamus|url=https://pubmed.ncbi.nlm.nih.gov/24623760/|journal=The Journal of Neuroscience: The Official Journal of the Society for Neuroscience|volume=34|issue=11|pages=3810–3820|doi=10.1523/JNEUROSCI.4343-13.2014|issn=1529-2401|pmc=3951688|pmid=24623760}}</ref> Additionally, CREB3L1 mRNA levels correspond with increased amounts of transcription of the AVP gene in the hypothalamus following a deficiency of sodium and as a consequence of diurnal rhythm in the SCN.<ref name=":4" /> Both full-length and constitutively active forms of CREB3L1 (CREB3L1CA) induce the expression of rat AVP promoter-luciferase reporter constructs whereas a dominant-negative mutant reduces expression. From this study, the researchers concluded that CREB3L1 is a regulator of AVP gene transcription in the hypothalamus and specifically within the PVH and SON.
-Arginine vasopressin stimulates the process of [[phosphorylation]] of [[Aquaporin 2|aquaporin 2 (AQP2)]] of renal tissue which contributes to the overall increased permeability of water in the collecting duct cells of the tissue. The phosphorylation of AQP2 leads to activation of the [[protein kinase A]] signaling pathway which amplifies the permeability of water by stimulating the rat equivalent of the [[urea transporter 1]] protein.<ref>{{Cite journal|last=Nishimoto|first=G.|last2=Zelenina|first2=M.|last3=Li|first3=D.|last4=Yasui|first4=M.|last5=Aperia|first5=A.|last6=Nielsen|first6=S.|last7=Nairn|first7=A. C.|date=1999-02-XX|title=Arginine vasopressin stimulates phosphorylation of aquaporin-2 in rat renal tissue|url=https://pubmed.ncbi.nlm.nih.gov/9950956/|journal=The American Journal of Physiology|volume=276|issue=2|pages=F254–259|doi=10.1152/ajprenal.1999.276.2.F254|issn=0002-9513|pmid=9950956}}</ref>
+Arginine vasopressin stimulates the process of [[phosphorylation]] of [[Aquaporin 2|aquaporin 2 (AQP2)]] of renal tissue which contributes to the overall increased permeability of water in the collecting duct cells of the tissue. The phosphorylation of AQP2 leads to activation of the [[protein kinase A]] signaling pathway which amplifies the permeability of water by stimulating the rat equivalent of the [[urea transporter 1]] protein.<ref>{{Cite journal|last1=Nishimoto|first1=G.|last2=Zelenina|first2=M.|last3=Li|first3=D.|last4=Yasui|first4=M.|last5=Aperia|first5=A.|last6=Nielsen|first6=S.|last7=Nairn|first7=A. C.|date=1999-02-XX|title=Arginine vasopressin stimulates phosphorylation of aquaporin-2 in rat renal tissue|url=https://pubmed.ncbi.nlm.nih.gov/9950956/|journal=The American Journal of Physiology|volume=276|issue=2|pages=F254–259|doi=10.1152/ajprenal.1999.276.2.F254|issn=0002-9513|pmid=9950956}}</ref>
 == Medical applications ==
@@ Line 40: / Line 40: @@
 ''Main Article:'' [[Vasopressin (medication)]]
-The functions of vasopressin make it useful for a variety of important medical applications. Since it plays a role in the regulation of many physiological functions, like regulation of water and sodium excretion, blood volume, [[vasoconstriction]], and response to [[Stress (biology)|stress]], vasopressin can be helpful in the treatment of conditions related to these functions.<ref>{{cite journal|last1=Gassanov|first1=Natig|last2=Semmo|first2=Nasser|last3=Semmo|first3=Mariam|date=2/17/2011|title=Arginine vasopressin (AVP) and treatment with arginine vasopressin receptor antagonists (vaptans) in congestive heart failure, liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion (SIADH)|url=https://link.springer.com/article/10.1007%2Fs00228-011-1006-7|journal=European Journal of Clinical Pharmacology|volume=67|page=333-346|doi=https://doi.org/10.1007/s00228-011-1006-7|access-date=2021-05-06}}</ref> These applications include treatment of [[nocturnal enuresis]], [[diabetes insipidus]], and [[Haemophilia A|hemophilia A]].<ref>{{Cite journal|last=Agrawal|first=Amit|last2=Singh|first2=Vishal K.|last3=Varma|first3=Amit|last4=Sharma|first4=Rajesh|date=April 2012|title=Therapeutic applications of vasopressin in pediatric patients|url=https://pubmed.ncbi.nlm.nih.gov/22565074/|journal=Indian Pediatrics|volume=49|issue=4|pages=297–305|doi=10.1007/s13312-012-0046-0|issn=0974-7559|pmid=22565074}}</ref> Additionally, it is used to treat some forms of [[Shock (circulatory)|shock]] including [[septic shock]] and [[vasodilatory shock]]. It is also used during surgery to decrease blood loss.<ref>{{Cite journal|last=Frishman|first=Gary|date=2009-02-XX|title=Vasopressin: If Some Is Good, Is More Better?|url=https://journals.lww.com/greenjournal/Citation/2009/02001/Vasopressin__If_Some_Is_Good,_Is_More_Better_.2.aspx|journal=Obstetrics & Gynecology|language=en-US|volume=113|issue=2 Part 2|pages=476–477|doi=10.1097/AOG.0b013e31819698bb|issn=0029-7844}}</ref>
+The functions of vasopressin make it useful for a variety of important medical applications. Since it plays a role in the regulation of many physiological functions, like regulation of water and sodium excretion, blood volume, [[vasoconstriction]], and response to [[Stress (biology)|stress]], vasopressin can be helpful in the treatment of conditions related to these functions.<ref>{{cite journal|last1=Gassanov|first1=Natig|last2=Semmo|first2=Nasser|last3=Semmo|first3=Mariam|date=2/17/2011|title=Arginine vasopressin (AVP) and treatment with arginine vasopressin receptor antagonists (vaptans) in congestive heart failure, liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion (SIADH)|url=https://link.springer.com/article/10.1007%2Fs00228-011-1006-7|journal=European Journal of Clinical Pharmacology|volume=67|issue=4|pages=333–346|doi=10.1007/s00228-011-1006-7|pmid=21327910|s2cid=1477146|access-date=2021-05-06}}</ref> These applications include treatment of [[nocturnal enuresis]], [[diabetes insipidus]], and [[Haemophilia A|hemophilia A]].<ref>{{Cite journal|last1=Agrawal|first1=Amit|last2=Singh|first2=Vishal K.|last3=Varma|first3=Amit|last4=Sharma|first4=Rajesh|date=April 2012|title=Therapeutic applications of vasopressin in pediatric patients|url=https://pubmed.ncbi.nlm.nih.gov/22565074/|journal=Indian Pediatrics|volume=49|issue=4|pages=297–305|doi=10.1007/s13312-012-0046-0|issn=0974-7559|pmid=22565074|s2cid=9836092}}</ref> Additionally, it is used to treat some forms of [[Shock (circulatory)|shock]] including [[septic shock]] and [[vasodilatory shock]]. It is also used during surgery to decrease blood loss.<ref>{{Cite journal|last=Frishman|first=Gary|date=2009-02-XX|title=Vasopressin: If Some Is Good, Is More Better?|url=https://dx.doi.org/10.1097%2FAOG.0b013e31819698bb|journal=Obstetrics & Gynecology|language=en-US|volume=113|issue=2 Part 2|pages=476–477|doi=10.1097/AOG.0b013e31819698bb|pmid=19155925|issn=0029-7844}}</ref>
 == References ==