Vasopressin receptor

The actions of vasopressin are mediated by stimulation of tissue-specific G protein-coupled receptors (GPCRs) called vasopressin receptors that are classified into the V1 (V1A), V2, and V3 (V1B) receptor subtypes.[1] These three subtypes differ in localization, function and signal transduction mechanisms.[2]

arginine vasopressin receptor 1A
Identifiers
SymbolAVPR1A
Alt. symbolsAVPR1
NCBI gene552
HGNC895
OMIM600821
RefSeqNM_000706
UniProtP37288
Other data
LocusChr. 12 q14-q15
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StructuresSwiss-model
DomainsInterPro
arginine vasopressin receptor 1B
Identifiers
SymbolAVPR1B
Alt. symbolsAVPR3
NCBI gene553
HGNC896
OMIM600264
RefSeqNM_000707
UniProtP47901
Other data
LocusChr. 1 q32
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StructuresSwiss-model
DomainsInterPro
arginine vasopressin receptor 2
Identifiers
SymbolAVPR2
Alt. symbolsDIR3, DIR
NCBI gene897
HGNC897
OMIM300538
RefSeqNM_000054
UniProtP30518
Other data
LocusChr. X q28
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StructuresSwiss-model
DomainsInterPro

Subtypes

There are three subtypes of vasopressin receptor: V1A (V1), V1B (V3) and V2.[1]

Subtype (symbol)Signaling pathwaysLocationFunction
genereceptor
IUPHARalternate
AVPR1AV1AV1G protein-coupled, phosphatidylinositol/calciumvascular smooth muscle, platelet, hepatocytes, myometriumvasoconstriction, myocardial hypertrophy, platelet aggregation, glycogenolysis, uterine contraction
AVPR1BV1BV3G protein-coupled, phosphatidylinositol/calciumanterior pituitary glandreleases ACTH, prolactin, endorphins
AVPR2V2V2Adenylyl cyclase/cAMPbasolateral membrane of collecting duct, vascular endothelium and vascular smooth muscle cellinsertion of AQP-2 water channels into apical membrane, induction of AQP-2 synthesis, releases von Willebrand factor and factor VIII, vasodilation

V1 receptor
Main article: Vasopressin receptor 1A

V1 receptors (V1Rs) are found in high density on vascular smooth muscle and cause vasoconstriction by an increase in intracellular calcium via the phosphatidyl–inositol-bisphosphate cascade.[1] Cardiac myocytes also possess V1R. Additionally V1R are located in brain, testis, superior cervical ganglion, liver, blood vessels, and renal medulla.[1]

V1R is present on platelets, which upon stimulation induces an increase in intracellular calcium, facilitating thrombosis. Studies have indicated that due to polymorphism of platelet V1R there is significant heterogeneity in the aggregation response of normal human platelets to vasopressin.[1]

V1Rs are found in kidney, where they occur in high density on medullary interstitial cells, vasa recta, and epithelial cells of the collecting duct.[1] Vasopressin acts on medullary vasculature through V1R to reduce blood flow to inner medulla without affecting blood flow to outer medulla. V1Rs on the luminal membrane of the collecting duct limit the antidiuretic action of vasopressin. Additionally, vasopressin selectively contracts efferent arterioles probably through the V1R, but not the afferent arteriole.[1]

V2 receptor
Main article: Vasopressin receptor 2

V2 receptor (V2R) differs from V1R primarily in the number of sites susceptible to N-linked glycosylation; the V1R has sites at both the amino-terminus and at the extracellular loop, whereas the V2R has a single site at the extracellular amino-terminus.[1]

The well known antidiuretic effect of vasopressin occurs via activation of V2R.[1] Vasopressin regulates water excretion from the kidney by increasing the osmotic water permeability of the renal collecting duct – an effect that is explained by coupling of the V2R with the Gs signaling pathway, which activates cAMP. The V2R continues to activate Gs after being internalized by β-arrestin rather than being desensitized. This internalized Gs signaling by V2R is explained by the receptors ability to form "mega-complexes" consisting of a single V2R, β-arrestin, and heterotrimeric Gs.[3] The increased intracellular cAMP in the kidney in turn triggers fusion of aquaporin-2-bearing vesicles with the apical plasma membrane of the collecting duct principal cells, increasing water reabsorption.[1]

V3 receptor
Main article: Vasopressin receptor 1B

The human V3 receptor (V3R, previously known as V1BR) is a G-protein-coupled pituitary receptor that, because of its scarcity, was only recently characterized.[1] The 424-amino-acid sequence of the V3R has homologies of 45%, 39%, and 45% with the V1R, V2R and oxytocin receptor (OTR), respectively. However, V3R has a pharmacologic profile that distinguishes it from the human V1R and activates several signaling pathways via different G-proteins, depending on the level of receptor expression.[1]

Function

Although all three of these proteins are G-protein coupled receptors (GPCRs), activation of AVPR1A and AVPR1B stimulate phospholipase C, while activation of AVPR2 stimulates adenylate cyclase. These three receptors for vasopressin have unique tissue distributions. AVPR1A are expressed in vascular smooth muscle cells, hepatocytes, platelets, brain cells, and uterus cells. AVPR1B are expressed in cells of the anterior pituitary and throughout the brain, especially in the pyramidal neurons of the hippocampal CA2 field. AVPR2 are expressed in the kidney tubule, predominantly in the distal convoluted tubule and collecting ducts, in fetal lung tissue and lung cancer, the last two being associated with alternative splicing. AVPR2 is also expressed in the liver where stimulation releases a variety of clotting factors into the bloodstream. In the kidney, AVPR2's primary function is to respond to arginine vasopressin by stimulating mechanisms that concentrate the urine and maintain water homeostasis in the organism. When the function of AVPR2 is lost, the disease Nephrogenic Diabetes Insipidus (NDI) results.[4]

Antagonists

Vasopressin receptor antagonists (VRAs) are drugs that block vasopressin receptors. Most commonly VRAs are used to treat hyponatremia caused by syndrome of inappropriate antidiuretic hormone secretion (SIADH), congestive heart failure (CHF) and cirrhosis.[2]

Somatostatin is a competitive inhibitor. [5]

Normally, when osmolality falls below its set point, plasma vasopressin levels become undetectable, and an aquaresis results. In SIADH, vasopressin release is not fully suppressed, despite hypotonicity.[2] In cirrhosis and CHF, impaired delivery of solute to the diluting sites or diminished glomerular filtration rate causes impairment of maximal water-excretory capacity, resulting in persistence of vasopressin release leading to water retention.[2]

Vasopressin receptor antagonists include the new class of "vaptan drugs" such as conivaptan, tolvaptan, mozavaptan, lixivaptan, satavaptan etc.

References
  1. Holmes CL, Landry DW, Granton JT (December 2003). "Science review: Vasopressin and the cardiovascular system part 1--receptor physiology". Crit Care. 7 (6): 427–34. doi:10.1186/cc2337. PMC 374366. PMID 14624682.
  2. Greenberg A, Verbalis JG (June 2006). "Vasopressin receptor antagonists". Kidney Int. 69 (12): 2124–30. doi:10.1038/sj.ki.5000432. PMID 16672911.
  3. Thomsen AR, Plouffe B, Cahill TJ, Shukla AK, Tarrasch JT, Dosey AM, Kahsai AW, Strachan RT, Pani B, Mahoney JP, Huang L, Breton B, Heydenreich FM, Sunahara RK, Skiniotis G, Bouvier M, Lefkowitz RJ (2016). "GPCR-G Protein-β-Arrestin Super-Complex Mediates Sustained G Protein Signaling". Cell. 166 (4): 907–19. doi:10.1016/j.cell.2016.07.004. PMC 5418658. PMID 27499021.
  4. Spanakis E, Milord E, Gragnoli C (December 2008). "AVPR2 variants and mutations in nephrogenic diabetes insipidus: review and missense mutation significance". J. Cell. Physiol. 217 (3): 605–17. doi:10.1002/jcp.21552. PMID 18726898. S2CID 20462680.
  5. Inhibition by somatostatin of the vasopressin-stimulated adenylate cyclase in a kidney-derived line of cells grown in defined medium. FEBS Letters. https://doi.org/10.1016/0014-5793(84)80304-X
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