UNIPROT:P01185 - FACTA Search

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Query: UNIPROT:P01185 (vasopressin)
23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Here we highlight just a few of the outstanding questions in the field of neurohypophysial hormones that we envisage will be addressed successfully in the new millennium. To begin, we focus on the regulation of receptors. Despite intensive investigation with new drugs, molecular modelling and transgenic models, the determinants of receptor selectivity remain elusive; there may even be more vasopressin or oxytocin receptor subtypes to be discovered. We discuss the controversy over the interesting studies that indicate modulation of oxytocin receptor-binding by steroids. Oxytocin and vasopressin release and action in the brain are discussed from several aspects. Dendritically released oxytocin acting locally is important for the milk ejection reflex, and similarly released vasopressin is important in regulating patterning of vasopressin neurone activity. Such dendritically released oxytocin and vasopressin is likely to be important in paracrine modulation of neural circuitry involved in neuroendocrine control, and for a range of behaviours. Is it possible that the whole range of behaviours that comprise 'social' (or 'anti-social') or 'maternal' behaviour can be engineered by modifying the expression of just these one or two peptides and their receptors? However, whether gene expression and knockout approaches will answer all the open questions about the real functions of oxytocin and vasopressin remains to be shown.
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PMID:Quo vadis neurohypophysial hormone research? 1079 31

Examination of the structure of [Arg(8)]-vasopressin receptors (AVPRs) and oxytocin receptors (OTRs) suggests that G protein-coupled receptor kinases (GRKs) and protein kinase C (PKC) are involved in their signal transduction. To explore the physical association of AVPRs and OTRs with GRKs and PKC, wild types and mutated forms of these receptor subtypes were stably expressed as green fluorescent protein fusion proteins and analyzed by fluorescence, immunoprecipitation, and immunoblotting. Addition of a C-terminal GFP tag did not interfere with ligand binding, internalization, and signal transduction. After agonist stimulation, PKC dissociated from the V(1)R, did not associate with the V(2)R, but associated with the V(3)R and the OTR. After AVP stimulation, only GRK5 briefly associated with AVPRs following a time course that varied with the receptor subtype. No GRK associated with the OTR. Exchanging the V(1)R and V(2)R C termini altered the time course of PKC and GRK5 association. Deletion of the V(1)R C terminus resulted in no PKC association and a ligand-independent sustained association of GRK5 with the receptor. Deletion of the GRK motif prevented association and reduced receptor phosphorylation. Thus, agonist stimulation of AVP/OT receptors leads to receptor subtype-specific interactions with GRK and PKC through specific motifs present in the C termini of the receptors.
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PMID:Dynamic interaction of human vasopressin/oxytocin receptor subtypes with G protein-coupled receptor kinases and protein kinase C after agonist stimulation. 1085 34

We investigated the developmental expression of vasopressin and oxytocin receptor and peptide mRNA using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot hybridization. Messenger RNAs for both vasopressin receptor subtypes V(1)a and V(2)were present in the telencephalon from embryonic day 12 to day 20. Both V(1)a and V(2)receptor mRNA increased on day 13 and then remained stable from embryonic day 13 to day 20. Messenger RNA for the vasopressin peptide was also detected in the telencephalon from day 12 to day 20, indicating that vasopressin could be synthesized within the rat cerebral cortex during rat embryonic development. Oxytocin receptor mRNA expression was also present in the telencephalon, but expression levels varied considerably from day 12 to day 20. No oxytocin mRNA expression was detected during rat telencephalon development. Temporal patterns of vasopressin receptor and vasopressin peptide mRNA expression along with oxytocin receptor mRNA suggest a temporal role for vasopressin- and oxytocin-mediated actions during rat telencephalon development.
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PMID:Vasopressin and oxytocin receptor mRNA expression during rat telencephalon development. 1102 77

A fundamental issue in molecular pharmacology is to define how agonist:receptor interaction differs from that of antagonist:receptor. The V(1a) receptor (V(1a)R) is a member of a family of related G-protein-coupled receptors that are activated by the neurohypophysial peptide hormone arginine-vasopressin (AVP). Here we define a short subdomain of the N-terminus of the V(1a)R from Glu(37) to Asn(47) that is an absolute requirement for binding AVP and other agonists. In marked contrast to the situation for agonists, deleting this segment has little or no effect on the binding of either peptide or non-peptide antagonists. In addition, we established that this subdomain was crucial for receptor activation and second messenger generation. The oxytocin receptor (OTR) also binds AVP with high affinity but exhibits a different pharmacological profile to the V(1a)R. Substitution of the N-terminus of the V(1a)R with the corresponding sequence from the OTR generated a chimeric receptor (OTR(N)-V(1a)R). The presence of the OTR N-terminus recovered high affinity agonist binding such that the OTR(N)-V(1a)R possessed almost wild-type V(1a)R pharmacology and signaling. Consequently, a domain within the N-terminus is required for agonist binding but it does not provide the molecular discriminator for subtype-selective agonist recognition. Cotransfection and peptide mimetic studies demonstrated that this N-terminal subdomain had to be contiguous with the receptor polypeptide to be functional. This study establishes that a segment of the V(1a)R N-terminus has a pivotal role in the mechanism of agonist binding and provides molecular insight into key differences between the interaction of agonists and antagonists with a peptide receptor family.
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PMID:Critical role of a subdomain of the N-terminus of the V1a vasopressin receptor for binding agonists but not antagonists; functional rescue by the oxytocin receptor N-terminus. 1106 89

The effects of cycloheximide and actinomycin on 8-bromo-cAMP (8-Br-cAMP) stimulated vasopressin and oxytocin release from the posterior pituitary and vasopressin mRNA content of the supraoptic nucleus were studied with perifused explants of the hypothalamo-neurohypophyseal system. 8-Br-cAMP stimulated vasopressin and oxytocin release from the explant for up to 6 h. Inhibition of protein synthesis by cycloheximide completely suppressed the response to 8-Br-cAMP. When gene transcription was inhibited by actinomycin, vasopressin release was stimulated by 8-Br-cAMP for approximately 2 h, but the response was not sustained. Vasopressin mRNA content was not changed by 8-Br-cAMP in the absence or presence of cycloheximide, but it was significantly decreased by simultaneous exposure to 8-Br-cAMP and actinomycin. Actinomycin alone did not change vasopressin mRNA content. Since other studies have demonstrated that cAMP stimulates vasopressin gene transcription, and since vasopressin mRNA content reflects the balance between gene transcription and mRNA degradation, the effect of actinomycin and 8-Br-cAMP on vasopressin mRNA content suggests that 8-Br-cAMP also decreased vasopressin mRNA stability and thereby induced a rapid turnover of vasopressin mRNA. The effects of cycloheximide and actinomycin on vasopressin and oxytocin release suggest that ongoing protein synthesis is required for stimulation of hormone release. Since the posterior pituitary hormone stores are not depleted with a stimulus for release that is even more potent than cAMP, it is possible that cycloheximide and actinomycin depleted smaller pools of the peptides such as those responsible for intranuclear vasopressin and oxytocin release. Further evidence that intranuclear release of vasopressin and oxytocin is a prerequisite for cAMP stimulation of vasopressin and oxytocin release was obtained by demonstrating that d(CH2)5-D-Tyr(Me)VAVP, a potent combined V1a/V2/oxytocin receptor antagonist blocked stimulation of vasopressin and oxytocin release by 8-Br-cAMP.
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PMID:cAMP stimulation of vasopressin and oxytocin release and regulation of vasopressin mRNA stability: role of auto-facilitation. 1116 41

The effects of the peptide hormone oxytocin are mediated by oxytocin receptors (OTRs) expressed by the target tissue. The OTR is a member of the large family of G-protein-coupled receptors. Defining differences between the interaction of agonists and antagonists with the OTR at the molecular level is of fundamental importance, and is addressed in this study. Using truncated and chimaeric receptor constructs, we establish that a small 12-residue segment in the distal portion of the N-terminus of the human OTR provides important epitopes which are required for agonist binding. In contrast, this segment does not contribute to the binding site for antagonists, whether peptide or non-peptide. It does, however, have a role in agonist-induced OTR signalling. Oxytocin is also an agonist at the vasopressin V(1a) receptor (V(1a)R). A chimaeric receptor (V(1a)R(N)-OTR) was engineered in which the N-terminus of the OTR was substituted by the corresponding, but unrelated, sequence from the N-terminus of the V(1a)R. We show that the V(1a)R N-terminus present in V(1a)R(N)-OTR fully restored both agonist binding and intracellular signalling to a dysfunctional truncated OTR construct. The N-terminal segment does not, however, contribute to receptor-selective agonism between the OTR and the V(1a)R. Our data establish a key role for the distal N-terminus of the OTR in providing agonist-specific binding epitopes.
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PMID:Identification of an extracellular segment of the oxytocin receptor providing agonist-specific binding epitopes. 1117 Nov 27

During the last two decades, it has become apparent that vasopressin and oxytocin, in addition to playing a role as peptide hormones, also act as neurotransmitters/neuromodulators. A number of arguments support this notion: (i) vasopressin and oxytocin are synthesized not only in hypothalamo-neurohypophysial cells, but also in other hypothalamic and extrahypothalamic cell bodies, whose axon projects to the limbic system, the brainstem and the spinal cord. (ii) Vasopressin and oxytocin can be shed from central axons as are classical neurotransmitters. (iii) Specific binding sites, i.e. membrane receptors having high affinity for vasopressin and oxytocin are present in the central nervous system. (iv) Vasopressin and oxytocin can alter the firing rate of selected neuronal populations. (v) In-situ injection of vasopressin and oxytocin receptor agonists and antagonists can interfere with behavior or physiological regulations. Morphological studies and electrophysiological recordings have evidenced a close anatomical correlation between the presence of vasopressin and oxytocin receptors in the brain and the neuronal responsiveness to vasopressin or oxytocin. These compounds have been found to affect membrane excitability in neurons located in the limbic system, hypothalamus, circumventricular organs, brainstem, and spinal cord. Sharp electrode intracellular recordings and whole-cell recordings, done in brainstem motoneurons or in spinal cord neurons, have revealed that vasopressin and oxytocin can directly affect neuronal excitability by opening non-specific cationic channels or by closing K(+) channels. These neuropeptides can also influence synaptic transmission, by acting either postsynaptically or upon presynaptic target neurons or axon terminals. Whereas, in cultured neurons, vasopressin and oxytocin appear to mobilize intracellular Ca(++), in brainstem slices, the action of oxytocin is mediated by a second messenger that is distinct from the second messenger activated in peripheral target cells. In this review, we will summarize studies carried out at the cellular level, i.e. we will concentrate on in-vitro approaches. Vasopressin and oxytocin will be treated together. Though acting via distinct receptors in distinct brain areas, these two neuropeptides appear to exert similar effects upon neuronal excitability.
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PMID:Vasopressin- and oxytocin-induced activity in the central nervous system: electrophysiological studies using in-vitro systems. 1124 Mar 11

The aim of this study was to evaluate the renal vascular effects of oxytocin in Sprague-Dawley rats and in Brattleboro heterozygous or homozygous rats, the latter being genetically deficient in vasopressin synthesis. Studies were performed in vitro, in the isolated kidney perfused in an open circuit with a Tyrode's solution. Oxytocin induced a concentration-dependent renal vasoconstriction in Sprague-Dawley rats, at rather high concentrations (EC50=170+/-39 nM, mean +/- SEM, n=6) with a maximum response amounting to 44% of that elicited by vasopressin (increase in renal vascular resistance: 11.5+/-0.9 mmHg min ml(-1) vs. 26.2+/-2.2 mmHg min ml(-1)). Oxytocin-evoked renal vasoconstriction was abolished by SR 49059, a selective vasopressin V1A receptor antagonist (10 nM), but not by d(CH2)5[Tyr(Me)2,Thr4,Orn8,Tyr-(NH2)9] vasotocin, an oxytocin receptor antagonist (10 nM). In the presence of SR 49059, oxytocin did not induce renal vasorelaxation. Oxytocin induced renal vasoconstriction in Brattleboro homozygotes and heterozygotes (EC50=59+/-12 nM and 262+/-110 nM; Emax=7.8+/-1.1 mmHg min ml(-1) and 6.9+/-0.4 mmHg min ml(-1), n=5 respectively) with characteristics similar as observed in Sprague-Dawley rats concerning partial agonist activity, low potency and antagonism by SR 49059. Responsiveness to vasopressin did not differ in Brattleboro homozygotes and heterozygotes (EC50 approximately 0.25 nM) and was similar as we reported in Sprague-Dawley rats. These findings indicate that high concentrations of oxytocin induce renal vasoconstriction in the rat by activating vasopressin V1A receptors. The low agonist activity makes it unlikely that oxytocin can substitute functionally for vasopressin at the renal vascular V1A receptor in Brattleboro homozygous rats which are deficient in endogenous vasopressin.
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PMID:High concentrations of oxytocin cause vasoconstriction by activating vasopressin V1A receptors in the isolated perfused rat kidney. 1133 Mar 29

Understanding of the molecular determinants responsible for antagonist binding to the oxytocin receptor should provide important insights that facilitate rational design of potential therapeutic agents for the treatment of preterm labor. To study ligand/receptor interactions, we used a novel photosensitive radioiodinated antagonist of the human oxytocin receptor, d(CH(2))(5) [Tyr(Me)(2),Thr(4),Orn(8),Phe(3(125)I,4N(3))-NH(2)9]vasotocin. This ligand had an equivalent high affinity for human oxytocin and V(1a) vasopressin receptors expressed in Chinese hamster ovary cells. Taking advantage of this dual specificity, we conducted photoaffinity labeling experiments on both receptors. Photolabeled oxytocin and V(1a) receptors appeared as a unique protein band at 70-75 kDa and two labeled protein bands at 85-90 and 46 kDa, respectively. To identify contact sites between the antagonist and the receptors, the labeled 70-75- and the 46-kDa proteins were cleaved with CNBr and digested with Lys-C and Arg-C endoproteinases. The fragmentation patterns allowed the identification of a covalently labeled region in the oxytocin receptor transmembrane domain III consisting of the residues Leu(114)-Val(115)-Lys(116). Analysis of contact sites in the V(1a) receptor led to the identification of the homologous region consisting of the residues Val(126)-Val(127)-Lys(128). Binding domains were confirmed by mutation of several CNBr cleavage sites in the oxytocin receptor and of one Lys-C cleavage site in the V(1a) receptor. The results are in agreement with previous experimental data and three-dimensional models of agonist and antagonist binding to members of the oxytocin/vasopressin receptor family.
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PMID:Direct identification of human oxytocin receptor-binding domains using a photoactivatable cyclic peptide antagonist: comparison with the human V1a vasopressin receptor. 1133

The aim of the present study was to clarify smooth muscle- and region-dependent distributions of the oxytocin receptor that mediates oxytocin-induced contraction in the nonpregnant porcine myometrium by means of mechanical and radioligand ([3H]-oxytocin) binding studies. In Krebs solution, oxytocin (0.1-300 nM) caused concentration-dependent contractions of the cornual myometrium, and the longitudinal muscle was more sensitive than the circular muscle. [Arg8]-vasopressin and [deamino-Cys1, D-Arg8]-vasopressin also contracted the myometrium, and the order of the potency was oxytocin > [Arg8]-vasopressin > [deamino-Cys(1), D-Arg(8)]-vasopressin. Treatment with a high concentration of oxytocin selectively inhibited the contraction of oxytocin and [Arg8]-vasopressin without affecting the responses of acetylcholine and high-K+. Selective cross inhibition was also observed in the presence of a high concentration of [Arg(8)]-vasopressin. The oxytocin-induced contraction was resistant to tetrodotoxin and atropine, but was reduced by verapamil or by the removal of external Ca2+, indicating that oxytocin has a direct action on smooth muscle cells and that extracellular Ca2+ plays an important role for the contraction. In Kumagai solution, oxytocin caused contraction of the cornual longitudinal muscle (-logEC50 = 8.5) but not the circular muscle. Longitudinal muscles of other regions (corpus and cervix) were also responsive to oxytocin, but the -logEC50 value differed from region to region (cornua > corpus = cervix). On the other hand, oxytocin failed to cause contraction of the corpus and cervical circular muscles. 3H-Oxytocin bound to crude membrane preparations of the myometrium in a concentration-dependent (0.084-2.7 nM) saturable manner. Scatchard analysis of equilibrium binding data revealed the presence of a single class of binding site with an apparent dissociation constant (Kd, 1.1-1.5 nM), but receptor density (Bmax) differed in the two muscle layer types (longitudinal muscle: circular muscle = 5:1) and tended to decrease from the cornua to the cervix. In conclusion, the receptor specific for oxytocin is present in the porcine myometrium and mediates the contractile responses of both oxytocin and [Arg8]-vasopressin. The distribution of the oxytocin receptors differs according to the type of muscle layer (longitudinal muscle > circular muscle) and the region of the uterus.
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PMID:Muscle layer- and region-dependent distributions of oxytocin receptors in the porcine myometrium. 1139 27

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