Vasopressin receptor

Last updated
arginine vasopressin receptor 1A
Identifiers
SymbolAVPR1A
Alt. symbols AVPR1
NCBI gene 552
HGNC 895
OMIM 600821
RefSeq NM_000706
UniProt P37288
Other data
Locus Chr. 12 q14-q15
arginine vasopressin receptor 1B
Identifiers
Symbol AVPR1B
Alt. symbolsAVPR3
NCBI gene 553
HGNC 896
OMIM 600264
RefSeq NM_000707
UniProt P47901
Other data
Locus Chr. 1 q32
arginine vasopressin receptor 2
Identifiers
Symbol AVPR2
Alt. symbolsDIR3, DIR
NCBI gene 897
HGNC 897
OMIM 300538
RefSeq NM_000054
UniProt P30518
Other data
Locus Chr. X q28

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]

Contents

Subtypes

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

Subtype (symbol)Signaling pathwaysLocationFunction
genereceptor
IUPHAR alternate
AVPR1A V1AV1G protein-coupled, phosphatidylinositol/calciumvascular smooth muscle, platelet, hepatocytes, myometriumvasoconstriction, myocardial hypertrophy, platelet aggregation, glycogenolysis, uterine contraction
AVPR1B V1BV3G protein-coupled, phosphatidylinositol/calciumanterior pituitary glandreleases ACTH, prolactin, endorphins
AVPR2 V2V2Adenylyl 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

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

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

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]

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.

Related Research Articles

G protein-coupled receptor Class of cell surface receptors coupled to G-Protein associated intracelular signaling

G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. Coupling with G proteins, they are called seven-transmembrane receptors because they pass through the cell membrane seven times. Ligands can bind either to extracellular N-terminus and loops or to the binding site within transmembrane helices. They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed.

G protein

G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they are bound to GTP, they are 'on', and, when they are bound to GDP, they are 'off'. G proteins belong to the larger group of enzymes called GTPases.

Vasopressin Mammalian hormone released from the pituitary gland

Vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travels down the axon of that cell, which terminates in the posterior pituitary, and is released from vesicles into the circulation in response to extracellular fluid hypertonicity (hyperosmolality). AVP has two primary functions. First, it increases the amount of solute-free water reabsorbed back into the circulation from the filtrate in the kidney tubules of the nephrons. Second, AVP constricts arterioles, which increases peripheral vascular resistance and raises arterial blood pressure.

Collecting duct system Kidney system

The collecting duct system of the kidney consists of a series of tubules and ducts that physically connect nephrons to a minor calyx or directly to the renal pelvis. The collecting duct system is the last part of nephron and participates in electrolyte and fluid balance through reabsorption and excretion, processes regulated by the hormones aldosterone and vasopressin.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is characterized by excessive unsuppressible release of antidiuretic hormone (ADH) either from the posterior pituitary gland, or an abnormal non-pituitary source. Unsuppressed ADH causes an unrelenting increase in solute-free water being returned by the tubules of the kidney to the venous circulation.

Demeclocycline

Demeclocycline, also known under the brand names Detravis, Meciclin, Mexocine, Clortetrin, is a tetracycline antibiotic which was derived from a mutant strain of Streptomyces aureofaciens.

Nephrogenic diabetes insipidus, also known as renal diabetes insipidus, is a form of diabetes insipidus primarily due to pathology of the kidney. This is in contrast to central or neurogenic diabetes insipidus, which is caused by insufficient levels of antidiuretic hormone. Nephrogenic diabetes insipidus is caused by an improper response of the kidney to antidiuretic hormone, leading to a decrease in the ability of the kidney to concentrate the urine by removing free water.

Vasopressin receptor 1A

Vasopressin receptor 1A (V1AR), or arginine vasopressin receptor 1A is one of the three major receptor types for vasopressin, and is present throughout the brain, as well as in the periphery in the liver, kidney, and vasculature.

Vasopressin receptor 1B

Vasopressin V1b receptor (V1BR) also known as vasopressin 3 receptor (VPR3) or antidiuretic hormone receptor 1B is a protein that in humans is encoded by the AVPR1B gene.

Vasopressin receptor 2

Vasopressin receptor 2 (V2R), or arginine vasopressin receptor 2, is a protein that acts as receptor for vasopressin. AVPR2 belongs to the subfamily of G-protein-coupled receptors. Its activity is mediated by the Gs type of G proteins, which stimulate adenylate cyclase.

Aquaporin 2

AQP2 is found in the apical cell membranes of the kidney's collecting duct principal cells and in intracellular vesicles located throughout the cell.

Arrestin

Arrestins are a small family of proteins important for regulating signal transduction at G protein-coupled receptors. Arrestins were first discovered as a part of a conserved two-step mechanism for regulating the activity of G protein-coupled receptors (GPCRs) in the visual rhodopsin system by Hermann Kühn, Scott Hall, and Ursula Wilden and in the β-adrenergic system by Martin J. Lohse and co-workers.

G protein-coupled receptor kinase

G protein-coupled receptor kinases are a family of protein kinases within the AGC group of kinases. Like all AGC kinases, GRKs use ATP to add phosphate to Serine and Threonine residues in specific locations of target proteins. In particular, GRKs phosphorylate intracellular domains of G protein-coupled receptors (GPCRs). GRKs function in tandem with arrestin proteins to regulate the sensitivity of GPCRs for stimulating downstream heterotrimeric G protein and G protein-independent signaling pathways.

G protein-coupled receptor kinase 2 Enzyme

G-protein-coupled receptor kinase 2 (GRK2) is an enzyme that in humans is encoded by the ADRBK1 gene. GRK2 was initially called Beta-adrenergic receptor kinase, and is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases that is most highly similar to GRK3(βARK2).

G<sub>s</sub> alpha subunit

The Gs alpha subunit is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein. Gsα is the founding member of one of the four families of heterotrimeric G proteins, defined by the alpha subunits they contain: the Gαs family, Gαi/Gαo family, Gαq family, and Gα12/Gα13 family. The Gs-family has only two members: the other member is Golf, named for its predominant expression in the olfactory system. In humans, Gsα is encoded by the GNAS complex locus, while Golfα is encoded by the GNAL gene.

Coagulation factor II receptor

Proteinase-activated receptor 1 (PAR1) also known as Protease-activated receptor 1 or coagulation factor II (thrombin) receptor is a protein that in humans is encoded by the F2R gene. PAR1 is a G protein-coupled receptor and one of four protease-activated receptors involved in the regulation of thrombotic response. Highly expressed in platelets and endothelial cells, PAR1 plays a key role in mediating the interplay between coagulation and inflammation, which is important in the pathogenesis of inflammatory and fibrotic lung diseases. It is also involved both in disruption and maintenance of endothelial barrier integrity, through interaction with either thrombin or activated protein C, respectively.

GRK5

G protein-coupled receptor kinase 5 is a member of the G protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases, and is most highly similar to GRK4 and GRK6. The protein phosphorylates the activated forms of G protein-coupled receptors to regulate their signaling.

Homologous desensitization

Homologous desensitization occurs when a receptor decreases its response to an agonist at high concentration. It is a process through which, after prolonged agonist exposure, the receptor is uncoupled from its signaling cascade and thus the cellular effect of receptor activation is attenuated.

A vasopressin receptor antagonist (VRA) is an agent that interferes with action at the vasopressin receptors. Most commonly VRAs are used in the treatment of hyponatremia, especially in patients with congestive heart failure, liver cirrhosis or SIADH.

AVP gene

Arginine Vasopressin (AVP) Gene is a gene whose product is proteolytically cleaved to produce vasopressin, 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. 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. 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.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 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. 1 2 3 4 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.