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Questions And Answer

• Discovery

  Vasopressin is a mammalian VP family peptide with vasopressor and antidiuretic actions. Disorders of VP and V2aR cause central and nephrogenic diabetes insipidus, respectively. Vasopressor and the antidiuretic effects of VP were first reported in 1895 and 1913, respectively. Arginine vasopressin (AVP) was isolated in 1951, and chemically synthesized in 1955.;

• Properties

  Mr 1084 (AVP), 1056 (LVP), 1068 (phenypressin); pI, 10.9 (AVP). The peptides are freely soluble in water. AVP solution in water at >10^-4M is stable for more than a year at -20°C, with increased stability under acidic conditions using acetic acid.;

• Structure

  The N-terminal six aa residues of the nonapeptides are flanked by two cysteine residues (positions 1 and 6) forming an intramolecular ring while the C-terminal extension with arginine or lysine residue confers a basic peptide property. The C-terminus is amidated. VPs are found only in mammals. Three peptides have been found . Most mammals, including humans, have AVP while LysineVP (LVP) and phenypressin were discovered from pigs and marsupials, respectively.
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• Gene, mRNA, and precursor

  The human preproAVP gene located on the short arm of chromosome 20 (20p13) consists of three exons and two introns.2 The oxytocin (OT) gene is located in the vicinity of the AVP gene in a tail-to-tail configuration, and they are transcribed in opposite directions. Human AVP mRNA has 595 bp encoding a signal peptide, a mature AVP with processing and amidation sites (GlyLys-Arg), a neurophysin, and a glycoprotein (copeptin) . Processing of the prohormone occurs in the acidic pH of large dense core vesicles. The neurophysin noncovalently binds with the mature peptide in the vesicles and functions as an intravesicular chaperone and carrier protein while the function of copeptin is still unknown. The AVP gene has glucocorticoid and cAMP responsive elements, and AP-1/2 regulatory elements in the promoter region. A downstream region of the AVP gene is also important as an enhancer. ;

• Agonists

  A number of peptide and orally-active nonpeptide agonists and antagonists have been investigated. Recent research to find coupling-selective ligands and to design bivalent ligands found that potent selective agonists are [Phe2 , Orn8 ]VP and F-180 (V1a agonists), d[Cha4 ]AVP (V1b agonist), and dDAVP and dVDAVP (V2a agonists). The selectivities vary between human and rat receptors.;

• Antagonists

  Potent selective antagonists are d(CH2)5[Tyr(Me)2 ] AVP and SR49059 (V1a antagonists); SSR149415 (V1b antagonist); and OPC31260, OPC41061, and SR121463 (V2 antagonists).;

• Receptors

  Three functional receptors have been identified (V1aR, V1bR, and V2aR). In humans, the length (aa residues), chromosomal location, and number of exons are as follows: V1aR, 418, 12q14-15, two exons; V1bR, 424, 1q32, two exons; and V2aR, 371, Xq28, three exons. AVP binds to three receptors with high affinity (Kd<2 nM). GPCRs including VP and OT receptors may also function as homo/hetero-dimers/oligomers.;

• Biological functions

  The most prominent function of AVP is the antidiuretic action through V2aR/aquaporin-2 (AQP2) in the inner medullary collecting duct of the kidney. AVP administration also induces a large increase in blood pressure. This effect is caused by vascular contraction, basoreflex, renin production, and aldosterone and glucocorticoid releases from the adrenal gland, all of which are mediated via V1aR. In addition, adrenocorticotropic hormone (ACTH) and catecholamine release via V1bR and body fluid retention via V2aR contribute to blood pressure regulation. In the pituitary, AVP synergistically controls the secretion of ACTH with corticotropin-releasing hormone (CRH). AVP also regulates metabolic function via V1aR and V1bR. In the central nervous system, AVP is involved in social behaviors, learning, memory, aggression, anxiety, depression, water and food intake, circadian rhythm, and thermoregulation.;

• Regulation of synthesis and release

  The synthesis and release of AVP are stimulated by the elevation of plasma osmolality and decreases in blood volume and blood pressure. Magnocellular AVP neurons receive signals of various neurotransmitters and neuromodulators from the circumventricular organs and medulla, including GABA, noradrenaline, dopamine, glutamic acid, atrial natriuretic peptide, and angiotensin II. In the parvocellular PVN, adrenalectomyincreases AVP synthesis while elevation is restored by dexamethasone administration. Direct regulation by androgen and estrogen is shown in the BNST and amygdala. Various peptide hormones (such as galanin, enkephalin, neuropeptide Y, vasoactive intestinal peptide, dynorphin) are colocalized in AVP neurons, and are involved in the regulation of AVP and OT release.;

• Clinical implications

  Approximately 90% of CNDI patients are males with mutations in the V2aR gene on the X-chromosome. Besides CNDI, gain-of-function mutations in V2aR cause nephrogenic syndrome of inappropriate antidiuresis (NSIAD), characterized by excessive sodium excretion, low plasma sodium concentration, and low plasma osmolality. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is typically associated with measurably elevated AVP levels and consequent V2aR hyperactivity.Due to the equimolar secretion with VP, plasma copeptin levels can be a prognostic marker in acute diseases, and a promising marker in the diagnosis of VP-related disorders.;

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