Disease relevance of AVPR1A

• To test whether the V(1)R is a marker for human essential hypertension, we sequenced the human AVPR1A gene and its 5; upstream region and found several DNA microsatellite motifs [1].
• V2 AVP receptor antagonists correct the impaired water excretion in rats with low-output CF, increase solute free water clearance, correct the hyponatremia in congestive CF patients, and normalize urinary concentrations of the aquaporin-2 (AQP-2) water channels [2].
• ERK activity is elevated in cells that line the cysts in animals with PKD, and AVP receptor antagonists reduce ERK activity and halt disease progression [3].
• Eutopic overexpression of vasopressin v1a receptor in adrenocorticotropin-independent macronodular adrenal hyperplasia [4].
• Potential therapeutic indications for AVP receptor antagonists comprise: 1) The blockade of V(1)-vascular AVP receptors in arterial hypertension, congestive heart failure, Raynaud's syndrome, peripheral vascular disease and dysmenorrhea [5].

Psychiatry related information on AVPR1A

• Given this comparative evidence for a role in inter-species variation in social behavior, we explored whether within our own species, variation in the human AVPR1A may contribute to individual variations in social behavior, with autism representing an extreme form of social impairment [6].
• Association between a vasopressin receptor AVPR1A promoter region microsatellite and eating behavior measured by a self-report questionnaire (Eating Attitudes Test) in a family-based study of a nonclinical population [7].
• OBJECTIVE: To examine family-based transmission of the number of 5' flanking arginine vasopressin V1a receptor (AVPR1A) microsatellites, which include [(GATA)(14)] and complex [(CT)(4)-TT-(CT)(8)-(GT)(24)] repeats, in probands with a prepubertal and early adolescent bipolar disorder phenotype (PEA-BP) [8].
• We examined whether genetic variations in the AVP receptor 1b gene (AVPR1b) could be associated with increased susceptibility to affective disorders using a gene-based association analysis of single-nucleotide polymorphisms (SNPs) [9].
• NRM pretreatment with AVP-receptor antagonist completely reversed AVP's effect on pain threshold in the NRM [10].

High impact information on AVPR1A

• The neurohypophysial hormone arginine vasopressin (AVP) is a cyclic nonpeptide whose actions are mediated by the stimulation of specific G protein--coupled membrane receptors pharmacologically classified into V1-vascular (V1R), V2-renal (V2R) and V3-pituitary (V3R) AVP receptor subtypes [11].
• In parallel, the abundance of vasopressin V1a receptors and the proportion of V1a receptor-labeled dendritic spines increase [12].
• Moreover, when Tyr115 is replaced by an Asp and a Phe, the amino acids naturally occurring in the V2 and in the OT receptor subtypes, the agonist selectivity of the V1a receptor switches accordingly [13].
• In this study, we investigated the functional roles of the V1a receptor in cardiovascular homeostasis using gene targeting [14].
• Taken together, these results indicate that the V1a receptor plays an important role in normal resting arterial BP regulation mainly by its regulation of circulating blood volume and baroreflex sensitivity [14].

Chemical compound and disease context of AVPR1A

• We examined the possibility that AVP and V1a receptors were involved in regulating cortisol production in a 49 year old man with ACTH-independent bilateral macronodular adrenocortical hyperplasia (AIMAH), and investigated the effects of a V1a receptor antagonist [15].
• The AVP-receptor antagonists, conivaptan, lixivaptan, and tolvaptan, are being studied for the treatment of hyponatremia [16].
• The importance of oxytocin and vasopressin in mechanisms of preterm labor is confirmed by the therapeutic effect in the condition of the oxytocin and vasopressin V1a receptor blocking oxytocin analogue, atosiban [17].
• The effect of relcovaptan (SR 49059), an orally active vasopressin V1a receptor antagonist, on uterine contractions in preterm labor [18].

Biological context of AVPR1A

• We genotyped two microsatellite polymorphisms from the 5' flanking region of AVPR1A for 115 autism trios and found nominally significant transmission disequilibrium between autism and one of the microsatellite markers by Multiallelic Transmission/Disequilibrium test (MTDT) that was not significant after Bonferroni correction [6].
• This difference in regional receptor expression as well as differences in social behavior may result from a highly variable repetitive sequence in the 5' flanking region of the V1a gene (AVPR1A) [6].
• Three other microsatellites are present in the 5; flanking DNA of the AVPR1A gene: a (GT)(25)dinucleotide repeat, a complex (CT)(4)-TT-(CT)(8)-(GT)(24)motif and a (GATA)(14)tetranucleotide repeat located respectively 3956 bp, 3625 bp and 553 bp upstream of the transcription start site [1].
• Similar genetic variation in the human AVPR1A may contribute to variations in human social behaviour, including extremes outside the normal range of behaviour and those found in autism spectrum disorders [19].
• Fluorescence in situ hybridization using a yeast artificial chromosome physically mapped AVPR1A to region 12q14-q15 [20].

Anatomical context of AVPR1A

• AVPR1A was localized by PCR analysis of a somatic cell hybrid panel to chromosome 12 [20].
• Molecular modeling of the results of site-directed mutagenesis experiments performed in CHO cells stably transfected with the human AVP receptor subtypes revealed that non-peptide antagonists establish key contacts with a few amino acid residues of the receptor subtypes that are different from those involved in agonist binding [21].
• This order was markedly different from that observed in rat vascular smooth muscle cells (A10), a well-established V1A receptor system [22].
• Tissue distribution of the human V1aR mRNA explored by Northern blot analysis of various human tissues or organs revealed the presence of a 5.5-kb mRNA transcript expressed in the liver and to a lesser degree in the heart, the kidney, and skeletal muscle [20].
• The vascular activity of arginine vasopressin (AVP) and selective AVP receptor antagonists was investigated in isolated arterial ring segments from human superior mesenteric arteries [23].

Associations of AVPR1A with chemical compounds

• Atosiban and SR 49059 both had a high affinity for the vasopressin V1a receptor (K(i) = 4.7 and 7.2 nmol/L, respectively, and a moderate one for the oxytocin receptor (K(i) = 397 and 340 nmol/L, respectively) [24].
• Novel approach to the design of synthetic radioiodinated linear V1A receptor antagonists of vasopressin [25].
• When cAMP was increased by treatment with 10 microM PGE1 and isobutylmethylxanthine, desensitization of the PGE1 receptor was observed but not of the AVP receptor [26].
• The behavioral effects of AVP are mediated through the AVP receptor 1a (AVPR1a), making the AVPR1a gene a reasonable candidate for autism susceptibility [27].
• Using alanine-scanning mutagenesis of the N-terminal juxtamembrane segment of the V1aR, we now establish that Glu54 (1.35) is critical for arginine vasopressin binding [28].

Physical interactions of AVPR1A

• Our data establish that a single residue, Arg46, is critical for AVP binding to the V1aR [29].
• Requirement of the third intracellular loop of the V2R for G(s) activation was identified by introducing V2R segments into the Gq coupled V1aR [Liu, J. and Wess, J. (1996) J. Biol. Chem. 271, 8772-8778]; the same approach recognized glutamate 231 and glutamine 225 at the amino terminus of loop 3i as being needed for signal transduction [30].

Regulatory relationships of AVPR1A

• In contrast, the V1a receptor mainly in the luminal membrane of distal nephron regulates basolateral V2 receptor-mediated action with regard to water and ion transport through the activation of G(q/11) and phosphoinositide turnover [31].
• Coexpression of the constitutively internalized R137HV2R mutant with V1aR was sufficient to promote cointernalization of V1aR in beta-arrestin-positive vesicles even in the absence of agonist stimulation [32].
• These data suggest that septal AVP enhances paternal responsiveness by a V1a receptor-mediated mechanism [33].

Other interactions of AVPR1A

• Within the family of human AVP receptors, the V2 AVP receptor has been cloned, but the structure of the human V1a and V1b AVP receptors remains unknown [34].
• Similar docking modes were found for the YM087/V1aR and YM087/V2R complexes, diverse from those of the YM087/OTR complexes, in agreement with the molecular affinity data [35].
• YM087 was computer-docked to V1aR, V2R and OTR using the AutoDock (Olson et al., Scripps Research Institute, La Jolla, USA) and subsequently relaxed using restrained simulated annealing and molecular dynamics, as implemented in AMBER program (Kollman et al., University of California, San Francisco, USA) [35].
• The V1a vasopressin receptor (V1aR) is a member of the neurohypophysial hormone subfamily of G protein-coupled receptors [28].
• In vivo and in vitro effects of AVP and V1a receptor antagonist on Cushing's syndrome due to ACTH-independent bilateral macronodular adrenocortical hyperplasia [15].

Analytical, diagnostic and therapeutic context of AVPR1A

• The V1a receptor subtype was expressed in the two parts of the gland, as shown by pharmacological studies and RT-PCR experiments [36].
• The presence of the OTR and V1aR protein was confirmed by immunohistochemistry [37].
• Controlled clinical trials now underway will help elucidate the role of AVP receptor antagonism in the treatment of hyponatremia [38].
• Microinjection of AVP-receptor antagonist into the AH inhibits the aggression of a resident hamster toward an intruder and diminishes aggression between hamsters placed into a neutral arena [39].
• Some AVP receptor antagonists have shown promising results in animal studies and small-scale clinical trials [40].

References