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Arginine Vasopressin (AVP) Gene is a gene that encodes vasopressin (also known as antidiuretic hormone, ADH), neurophysin II, and a glycoprotein. AVP is present on chromosome 20 in humans and plays a role in homeostatic regulation. Expression of AVP is regulated by the TTFL, which is an important part of the circadian system. AVP has important implications in the medical field due to the roles its products have in the body.

Discovery

Vasopressin

The discovery of the AVP gene began with 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.[1] 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.[2]

The discovery and separation of vasopressin allowed for subsequent research on its structure and function. In 1951, Turner and colleagues uncovered the amino acid sequence behind the hormone. The nine amino acid structure was composed of phenylalanine, tyrosine, proline, glutamic acid, aspartic acid, glycine, arginine, cystine, and ammonia.[3] Following this discovery, Vincent de Vigneaud was able to synthesize a synthetic form of vasopressin in a laboratory setting. De Vigneaud specifically noted that his final product had the same activity and composition ratios as that of naturally occurring vasopressin.[4]

AVP gene

The final stage of research leading to the discovery of the AVP gene began when Gainer and colleagues found a precursor protein to vasopressin in 1977.[5] 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.[6] 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) each was responsible for.[7]

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 three domains spanning 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.[7]

Visualization of the AVP Gene Structure

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 SCN.[8] 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.[9] 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.[8]

Transcription of the AVP gene to produce AVP mRNA has daily rhythms, with mRNA levels peaking during the subjective day and reaching its 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.[8]

Function

AVP, or arginine vasopressin, is primarily known for its role as a mammalian molecular output.[9][10] The most common product of AVP is vasopressin which is a neurohypophysial hormone that is important in homeostatic mechanisms and processes and its other products are neurophysin and glycoprotein. AVP is produced in a specific type of neuron called magnocellular neurons (MCNs), which are located in the hypothalamus.[10] In mammals, the AVP gene is transcribed in the SCN, which is also in the hypothalamus, under the regulation of the genetic transcription-translation feedback loop (TTFL). The TTFL is an essential part of circadian clocks since it is the molecular machinery that controls the expression of clock genes.[11] The AVP mRNA transcript travels from the hypothalamus to the posterior pituitary where it is stored and released into the bloodstream as a result of environmental stressors, like dehydration.[12]

A component of this circadian clock mechanism to note is that the AVP gene, and resulting AVP protein, do not need a PAS or BHLH domain, which mediate the various interactions that occur between transcription factors. This means that the AVP gene and resulting protein are structurally stable and can self-sustain binding processes and molecular transportation.[citation needed]

The transcription of the AVP gene commonly results in the vasopressin peptide that can bind to one of three vasopressin receptors: AVPR1A, AVPR1B, and AVPR2. When vasopressin binds to AVPR1A, a G-protein coupled receptor (GPCR), phospholipase C becomes activated.[13][14] This pathway typically involves regulating vasoconstriction. When vasopressin binds to AVPR1B, a GPCR, the phosphatidylinositol-calcium second messenger system is stimulated. This signaling pathway is important in regulating homeostasis and the amount of water, glucose, and salts within the blood via ACTH release and storage.[15] When vasopressin binds to AVPR2, a 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 concentrating liquid toxins in urine.[16]

AVP gene in rats

Within rats, the AVP gene is important for the regulation of various processes within the excretory system and smooth muscle cells. The AVP gene and arginine vasopressin are commonly colocalized with oxytocin due to how synaptic transmission of oxytocin influences the AVP mRNA expression.[17]

In a clinical study, the AVP gene expression in rats is regulated by the cAMP responsive element-binding protein-3 like-1 (CREB3L1). The CREB3L1 is activated when the N-terminal  of the AVP gene is cleaved during translocation from the Golgi to the nucleus.[18] Additionally, the 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.[18] 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.

The arginine vasopressin stimulates the process of phosphorylation of aquaporin 2 (AQP2) at renal tissue, which contributes to the overall increased permeability of water in the collecting duct cells of the tissue.[19] 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.[citation needed]

Medical applications

Vasopressin, a product of the AVP gene, has a variety of important medical applications. These applications include treatment of nocturnal enuresis, diabetes insipidus, and hemophilia A.[20] Additionally, it is used to treat some forms of shock, such as septic shock and vasoplegic shock. It is also used during surgery to decrease blood loss.[21]  

References

  1. ^ 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.
  2. ^ 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.
  3. ^ 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. ISSN 0021-9258. PMID 14850440.
  4. ^ 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.
  5. ^ 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. doi:10.1126/science.65791. ISSN 0036-8075. PMID 65791.
  6. ^ 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. doi:10.1038/295299a0. ISSN 0028-0836. PMID 6276766.
  7. ^ 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. ISSN 0261-4189. PMID 6315416.
  8. ^ 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.
  9. ^ 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. doi:10.3389/fnins.2019.00139. ISSN 1662-4548. PMC 6397828. PMID 30858797.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ a b "Vasopressin neurotransmission and the control of circadian rhythms in the suprachiasmatic nucleus". Progress in Brain Research. 119: 351–364. 1999-01-01. doi:10.1016/S0079-6123(08)61580-0. ISSN 0079-6123.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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. ISSN 0021-9258. PMID 8106369.
  16. ^ 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. PMID 14624682.
  17. ^ 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. doi:10.1126/science.3406747. ISSN 0036-8075. PMID 3406747.
  18. ^ 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.
  19. ^ 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)
  20. ^ 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.
  21. ^ 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. {{cite journal}}: Check date values in: |date= (help)
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