Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vasopressin, one of the first characterized neuropeptides, has a wide spectrum of biological action, acting on distinct tissues. Indeed, it is involved in water retention, glucose metabolism, blood pressure and its implication in the CNS has also been described. This diversity of effects on mammalian tissues is mediated by distinct G protein-coupled receptors, acting via distinct second messenger pathways. This receptor family has been subtyped by pharmacological studies, as V1a receptor whose action is mediated by intracellular calcium mobilization, and V2 receptor which is linked to adenylyl cyclase. Since so many essential functions were ensured by vasopressin, molecular characterization of its receptors became soon a great challenge. This prompted us to isolate the cDNA of AVP V1a receptor as the first member of this family, by expression cloning. Intracellular calcium mobilization was therefore assayed after rat liver mRNA injection into Xenopus oocytes. A single clone, encoding a functional AVP receptor corresponding to the V1a subtype was finally characterized as a G protein-coupled receptor. Furthermore, we used homology cloning strategy in order to clone the AVP V2 subtype from a rat kidney cDNA library. A putative receptor clone was finally characterized as the rat V2 receptor cDNA by binding and cAMP increase experiments, on transfected cells.
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PMID:Molecular cloning and expression of rat V1a and V2 arginine vasopressin receptors. 851 67

The coding region of the human vasopressin type 2 receptor gene bears mutations in the individuals affected with congenital nephrogenic diabetes insipidus, a disease characterized by the inability of the kidney to concentrate urine in response to vasopressin. Although it is assumed that the mutations result in loss of receptor function, proof of this hypothesis is lacking. We introduced one of these naturally occurring point mutations leading to a single amino acid change (Arg137-->His) into wild type cDNA. The mutant protein was expressed, and the functional properties of the receptor were examined. The mutant receptor exhibited an unaltered binding affinity for vasopressin compared to the wild type but failed to stimulate the Gs/adenylyl cyclase system. These data provide biochemical proof that the mutant receptor is the cause of the disease.
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PMID:Nephrogenic diabetes insipidus. A V2 vasopressin receptor unable to stimulate adenylyl cyclase. 851 44

The peptide hormones angiotensin II and vasopressin play a major role in water and electrolyte homeostasis. These peptides act on membrane bound receptors, which all belong to the large family of G protein coupled receptors. The receptors for angiotensin II are divided into 2 groups: the AT1 receptors, which are responsible for transducing the majority if not all actions of angiotensin II. The primary structure of this receptor has been identified by molecular cloning of the cDNA in many species and is represented by two isoforms (AT1A and AT1B) in rodent. This receptor is specifically coupled to a G protein of the Gq family, which activates a phospholipase C producing two second messengers involved in protein phosphorylation and calcium mobilization. The sequences or amino-acids involved in the binding site of peptidic agonists or non peptidic antagonists and in receptor activation and G protein coupling have been identified; the AT2 receptor primary sequence has also been identified, but the physiological role and the signaling mechanisms of this receptor are still unknown. The vasopressin receptors can be divided in three classes depending on their pharmacological properties, their tissular distribution and their coupling mechanisms. The primary structure of all 3 types of receptors has been elucidated. The V1a receptor is ubiquitous and transduces the vasoconstrictive effect of vasopressin by activating a phospholipase C, like the AT1 receptors; the V2 receptor is involved in water reabsorption in the kidney and is coupled to a GS protein activating an adenylyl cyclase; the V3 or V1b receptor is expressed in the pituitary, where it regulates the ACTH secretion, via the activation of a phospholipase C. These two family of G protein coupled receptors illustrate the structural and functional diversity of the receptors for peptidic hormones.
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PMID:[Comparative study of the structure and molecular functions of angiotensin II and vasopressin receptors]. 859 Feb 17

The vasopressin receptor family is unique among all classes of peptide receptors in that its individual members couple to different subsets of G proteins. The V1a vasopressin receptor, for example, is preferentially linked to G proteins of the Gq/11 class (biochemical response: stimulation of phosphatidylinositol hydrolysis), whereas the V2 vasopressin receptor is selectively coupled to Gs (biochemical response: stimulation of adenylyl cyclase). To elucidate the structural basis underlying this functional heterogeneity, we have systematically exchanged different intracellular domains between the V1a and V2 receptors. Transient expression of the resulting hybrid receptors in COS-7 cells showed that all mutant receptors containing V1a receptor sequence in the second intracellular loop were able to activate the phosphatidylinositol pathway with high efficiency. On the other hand, only those hybrid receptors containing V2 receptor sequence in the third intracellular loop were capable of efficiently stimulating cAMP production. These findings suggest that the differential G protein coupling profiles of individual members of a structurally closely related receptor subfamily can be determined by different single intracellular receptor domains.
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PMID:Different single receptor domains determine the distinct G protein coupling profiles of members of the vasopressin receptor family. 862 13

Inactivating mutations in distinct G protein-coupled receptors (GPCRs) are currently being identified as the cause of a steadily growing number of human diseases. Based on previous studies showing that GPCRs are assembled from multiple independently stable folding units, we speculated that such mutant receptors might be functionally rescued by 'supplying' individual folding domains that are lacking or misfolded in the mutant receptors, by using a co-expression strategy. To test the feasibility of this approach, a series of nine mutant V2 vasopressin receptors known to be responsible for X-linked nephrogenic diabetes insipidus were used as model systems. These mutant receptors contained nonsense, frameshift, deletion or missense mutations in the third intracellular loop or the last two transmembrane helices. Studies with transfected COS-7 cells showed that none of these mutant receptors, in contrast to the wild-type V2 receptor, was able to bind detectable amounts of the radioligand, [3H]arginine vasopressin, or to activate the G(S)/adenylyl cyclase system. Moreover, immunological studies demonstrated that the mutant receptors were not trafficked properly to the cell surface. However, several of the nine mutant receptors regained considerable functional activity upon co-expression with a C-terminal V2 receptor peptide spanning the sequence where the various mutations occur. In many cases, the restoration of receptor activity by the co-expressed receptor peptide was accompanied by a significant increase in cell surface receptor density. These findings may lead to the design of novel strategies in the treatment of diseases caused by inactivating mutations in distinct GPCRs.
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PMID:Functional rescue of mutant V2 vasopressin receptors causing nephrogenic diabetes insipidus by a co-expressed receptor polypeptide. 863 61

Pulsatile secretion of endometrial prostaglandin (PG)F2 alpha is stimulated by oxytocin (OT) during late diestrus in domestic ruminants (i.e., cattle, sheep and goats) and results in corpus luteum (CL) regression leading to the onset of a new estrous cycle. Pulsatile PGF2 alpha release is also responsible for CL regression in swine, but the stimulus for its secretion from the uterine endometrium is not known. We propose that OT binds to specific OT receptors (OTR) on the endometrium to stimulate phosphoinositide (PI) hydrolysis, thereby activating the inositol trisphosphate (IP3)-diacylglycerol (DAG) second-messenger system to promote pulsatile PGF2 alpha secretion. Exogenous OT administered to cyclic gilts during late diestrus (days 10-16) decreased interestrous interval in three of four experiments. However, OT did not promote CL regression in hysterectomized gilts indicating that the effect of OT was uterine-dependent. Circulating concentrations of 13,14-dihydro-15-keto PGF2 alpha (the major stable metabolite of PGF2 alpha) were increased (p < 0.01) 10 min after i.v. injection of OT on days 14 and 16 in cyclic gilts and on days 10-16 in pregnant gilts, but the magnitude of the response to OT on all days in pregnant gilts was markedly reduced compared to the response in cyclic gilts on days 14 and 16. Mean density and Kd of OTR detected on endometrium of cyclic pigs 15 days post-estrus were 29.2 +/- 5.5 fmol/mg protein and 1.59 +/- 0.23 nM, respectively. Density of OTR was correlated with OT-stimulated PI hydrolysis (r = 0.83, p < 0.05) and PGF2 alpha secretion (r = 0.87, p < 0.10). Endometrial IP3 was increased within 30 seconds after OT treatment and preceded the increase in PGF2 alpha release stimulated by OT. Endometrial PI hydrolysis and PGF2 alpha secretion were similarly increased by AIF4-(phospholipase C activator), but not by cholera toxin (adenylyl cyclase activator). Although OT binding to OTR could be displaced by lysine-vasopressin and lysine-vasopressin stimulated PI hydrolysis, lysine-vasopressin did not stimulate PGF2 alpha release. Distinct receptors for OT and lysine-vasopressin on pig endometrium were confirmed by treatment with 100 nM OT + 100 nM lysine-vasopressin which stimulated PI hydrolysis more than 100-200 nM OT or lysine-vasopressin alone. These results support the hypothesis that OT stimulates phospholipase C to hydrolyze PI, yielding IP3 and DAG second-messengers which promote endometrial PGF2 alpha release during CL regression in pigs.
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PMID:A proposed role for oxytocin in regulation of endometrial prostaglandin F2 alpha secretion during luteolysis in swine. 871 96

The carboxyl terminus of the G protein alpha subunit is a key determinant of the fidelity of receptor activation. We have previously shown that the Gq alpha subunit (alpha q) can be made to respond to alpha i-coupled receptors by replacing its carboxyl terminus with the corresponding alpha i2, alpha o, alpha z residues. We now extend these findings in three ways: 1) carboxyl-terminal mutations of alpha q/alpha i chimeras show that the critical amino acids are in the -3 and -4 positions, 2) exchange of carboxyl termini between alpha q and alpha z allows activation by receptors appropriate to the carboxyl-terminal residues, and 3) we identify receptors that either do or do not activate the expected carboxyl-terminal chimeras (alpha q/alpha i, alpha q/alpha s, alpha s/alpha q). Replacement of the five carboxyl-terminal amino acids of alpha q with the alpha s sequence permitted an alpha s-coupled receptor (the V2 vasopressin receptor but not the beta 2-adrenergic receptor) to stimulate phospholipase C. Replacement of the five carboxyl-terminal amino acids of alpha z with residues of alpha q permitted certain alpha q-coupled receptors (bombesin and V1a vasopressin receptors but not the oxytocin receptor) to stimulate adenylyl cyclase. Thus, the relative importance of the G alpha carboxyl terminus in permitting coupling to a new receptor depends on the receptor with which it is paired. These studies refine our understanding and provide new tools with which to study the fidelity of receptor/G alpha activation.
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PMID:Carboxyl-terminal mutations of Gq alpha and Gs alpha that alter the fidelity of receptor activation. 886 34

Previous studies have demonstrated that both the V2-receptor agonist, 1-desamino-8-D-arginine vasopressin (dDAVP), and the V1a-receptor agonist, [Phe2, Orn8]vasotocin (PO-VT), increase intracellular calcium concentration ([Ca2+]i) in the rat inner medullary collecting duct (IMCD). The present studies were done to clarify the receptor subtype(s) responsible for calcium mobilization. Measurements of [Ca2+]i, using fura 2 in microdissected IMCD segments, confirmed that arginine vasopressin (AVP), dDAVP, and PO-VT stimulate an increase in [Ca2+]i and that the response to all three agents could be blocked by the specific V2-receptor antagonist, [d(CH2)5(1),D-Ile2, Ile4, Arg8]vasopressin (II-VP). These results would suggest that all three agents acted through the V2 receptor. Furthermore, we showed that PO-VT increased cAMP production in IMCD suspensions and water permeability in isolated perfused tubules. These responses were also blocked by II-VP, indicating that PO-VT is also a V2 agonist in the IMCD. Finally, we utilized the quantitative reverse transcription-polymerase chain reaction technique of Wiesner (Nucleic Acids Res. 20: 5863-5864, 1992) to evaluate V1a and V2 mRNA levels in rat collecting duct. In terminal IMCD, we estimated > 30 copies/cell for V2 receptor mRNA but less than 1 copy/cell of V1a receptor mRNA, thus there is littler or no V1a mRNA expression in the terminal IMCD. These results suggest that calcium mobilization in response to vasopressin analogues is associated with the V2 receptor and that the V2 receptor is linked to both adenylyl cyclase and calcium mobilization in the rat IMCD.
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PMID:Evidence for dual signaling pathways for V2 vasopressin receptor in rat inner medullary collecting duct. 896 40

SR 121463A, a potent and selective, orally active, nonpeptide vasopressin V2 receptor antagonist, has been characterized in several in vitro and in vivo models. This compound displayed highly competitive and selective affinity for V2 receptors in rat, bovine and human kidney (0.6 < or = Ki [nM] < or = 4.1). In this latter preparation, SR 121463A potently antagonized arginine vasopressin (AVP)-stimulated adenylyl cyclase activity (Ki = 0.26+/-0.04 nM) without any intrinsic agonistic effect. In autoradiographic experiments performed in rat kidney sections, SR 121463A displaced [3H]AVP labeling especially in the medullo-papillary region and confirmed that it is a suitable tool for mapping V2 receptors. In comparison, the nonpeptide V2 antagonist, OPC-31260, showed much lower affinity for animal and human renal V2 receptors and lower efficacy to inhibit vasopressin-stimulated adenylyl cyclase (Ki in the 10 nanomolar range). Moreover, OPC-31260 exhibited a poor V2 selectivity profile and can be considered as a V2/V1a ligand. In normally hydrated conscious rats, SR 121463A induced powerful aquaresis after intravenous (0.003-0.3 mg/kg) or oral (0.03-10 mg/kg) administration. The effect was dose-dependent and lasted about 6 hours at the dose of 3 mg/kg p.o. OPC-31260 had a similar aquaretic profile but with markedly lower oral efficacy. The action of SR 121463A was purely aquaretic with no changes in urine Na+ and K+ excretions unlike that of known diuretic agents such as furosemide or hydrochlorothiazide. In addition, no antidiuretic properties have been detected with SR 121463A in vasopressin-deficient Brattleboro rats. Thus, SR 121463A is the most potent and selective, orally active V2 antagonist yet described and could be a powerful tool for exploring V2 receptors and the therapeutical usefulness of V2 blocker aquaretic agents in water-retaining diseases.
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PMID:Characterization of SR 121463A, a highly potent and selective, orally active vasopressin V2 receptor antagonist. 898 18

The purpose of this study was to characterize the role of M2 muscarinic receptors in inhibiting relaxant effects of drugs that stimulate cyclic AMP (cAMP) accumulation in the guinea pig ileum. We investigated the ability of oxotremorine-M (oxo-M) to inhibit cAMP accumulation in the presence of agonists that stimulate adenylyl cyclase in other cells and tissues. Appreciable stimulation of cAMP (> 50% over basal levels) was achieved with forskolin and maximally effective concentrations of isoproterenol, cicaprost, prostaglandin E1, prostaglandin E2 and prostaglandin I2, with the stimulation over basal levels of cAMP being 14.9-, 2.51-, 2.45-, 2.27-, 2.28- and 1.52-fold, respectively. Moderate or no cAMP stimulation was observed with dopamine, 5-hydroxytryptamine, 5-methoxytryptamine, dimaprit, vasoactive intestinal peptide, SKF-38393, 2-chloroadenosine, CGS-21680, prostaglandin D2, secretin and vasopressin. Oxo-M (1 microM) inhibited cAMP accumulation by 35% under basal conditions. Oxo-M inhibited specific agonist-stimulated cAMP levels by 20 to 70%. However, oxo-M caused little or no inhibition of specific prostaglandin I2- and cicaprost-stimulated cAMP levels (5 and 0%, respectively). In general, there was a correlation between the abilities of the various agonists to stimulate cAMP accumulation and to cause relaxation of the isolated ileum, with an exception being cicaprost. Experiments were carried out with isolated ileum to determine whether activation of M2 receptors inhibited the relaxant effects of the various agonists. In these experiments, the ileum was first treated with N-(2-chloroethyl)-4-piperidinyl diphenylacetate to selectively inactivate M3 receptors. After this treatment phase, contractile responses to oxotremorine-M were measured in the presence of histamine and a given relaxant agent. These measurements were repeated in the presence of the M2-selective antagonist AF-DX 116. Analysis of the data showed that part of the contractile response to oxotremorine-M could be attributed to an M2-mediated inhibition of the relaxation. This M2 component of the contractile response was greatest when forskolin or isoproterenol was used as the relaxant agent. In contrast, little or no M2 response was measured in the presence of dopamine and cicaprost.
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PMID:M2 muscarinic receptor inhibition of agonist-induced cyclic adenosine monophosphate accumulation and relaxation in the guinea pig ileum. 899 96


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