UNIPROT:P01178 - FACTA Search

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Query: UNIPROT:P01178 (oxytocin)
15,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Luteinizing hormone is the major regulator of Leydig cell differentiation and steroidogenic function. A number of hormones produced by the Leydig cell (e.g. estrogen, angiotensin, CRF, vasopressin) and the tubular compartment (inhibin, TGF beta), can influence both acute and long-term actions of LH. Conversely, hormones produced in the Leydig cells modulate tubular function (e.g. androgen, beta-endorphin, oxytocin). The LH stimulatory event can be negatively influenced by the action of angiotensin II through the guanyl nucleotide inhibitory unit of adenylate cyclase. We have recently discovered an action of corticotrophin releasing hormone through specific high-affinity low-capacity receptors in the Leydig cells which involves a pertussis toxin insensitive guanyl nucleotide regulatory unit with interaction between signalling pathways and resulting inhibition of LH induced cAMP generation and consequently of steroidogenesis. In contrast to other tissues the CRF receptor in the Leydig cells did not couple to Gs. CRF action is exerted through direct or indirect action of protein kinase C, at the level of the catalytic subunit of adenylate cyclase. Physiological increases in endogenous LH cause positive regulation of membrane receptors and steroidogenesis, while major elevations in circulating gonadotropin can induce down-regulation of LH receptors and desensitization of steroid responses in the adult cell. Gonadotropin-induced desensitization in adult rat tests include an estrogen mediated steroidogenic lesion of the microsomal enzymes 17 alpha-hydroxylase/17,20-desmolase. For further understanding of the regulation of this key enzyme of the androgen pathway the rat P450(17) alpha cDNA was cloned and sequenced. This cDNA expressed in COS-1 cells 17 alpha-hydroxylase/17,20-desmolase activities. From the deduced amino acid sequence, two transmembrane regions were identified, a signal peptide for insertion in the ER, and a 2nd transmembrane region separated from the first by 122 amino acids. The carboxy terminal non-transmembrane region possesses 4 hydrophobic clefts, of which cleft II would contain the putative steroid binding site for both hydroxylase and lyase activities. The rat cDNA was employed to evaluate the hormonal regulation of mRNA levels in adult and fetal Leydig cells. Low dose hCG treatment caused an early increase in mRNA levels followed by a return to control values at later times, while with higher desensitizing doses the initial increase in mRNA was followed by a marked reduction in mRNA at 24 h and a small recovery at 48 h. Fetal rat Leydig cells treated with E2 showed a 70% decrease in P450 mRNA levels, and testosterone production closely followed the changes in mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:LH action in the Leydig cell: modulation by angiotensin II and corticotropin releasing hormone, and regulation of P450(17) alpha mRNA. 269 45

We describe here the binding and functional properties of a cloned human oxytocin receptor (OTR). We established a transient OTR expression system on COS-1 cells, which do not express vasopressin receptors. With the transfected cells and [3H]oxytocin, the dissociation constant (Kd) of OTR to oxytocin was 6.0 +/- 1.1 nmol/l; the binding properties of several oxytocin-related peptides were also examined. The functional properties of OTR were determined by an electrophysiological method, using a Xenopus laevis oocyte injected with in vitro transcribed OTR mRNA. These two methods showed that [Phe2,Orn8]vasotocin, a vasopressin agonist, was an OTR antagonist. A combination of these methods using cloned OTR cDNA is a novel and effective method for the investigation of oxytocin-related ligands.
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PMID:Molecular characterization of a cloned human oxytocin receptor. 792 Dec 28

Arginine vasopressin modulates the release of adrenocorticotropic hormone, beta-endorphin, and prolactin from the anterior pituitary. Release is mediated by the V1b receptor through the mobilization of intracellular Ca2+ by phosphatidylinositol hydrolysis. In contrast to its well characterized peripheral actions, such as antidiuresis, contraction of vascular smooth muscle, and stimulation of hepatic glycogenolysis, the exact site and mechanism of vasopressin action in the pituitary remain unclear. This is largely due to a lack of information on the molecular identity and exact localization of the V1b receptor. This lack prompted us to try to isolate this receptor subtype. Here we report the molecular cloning and functional expression of a complementary DNA encoding the human V1b receptor. The deduced 424-amino acid sequence of the receptor has highest overall homology with the V1a, V2, and oxytocin receptors, with homologies of 45, 39, and 45%, respectively. The receptor expressed in COS-1 cells has a single binding site for arginine vasopressin with a Kd of 0.17 +/- 0.04 nM. It binds various agonists and antagonists of vasopressin with affinities distinct from those of V1a and V2 receptors but consistent with those anticipated for the V1b receptor on the basis of the pharmacological studies. Furthermore, arginine vasopressin evoked calcium-dependent chloride current in Xenopus oocytes transfected with the receptor, which was not affected by a V1a/V2 antagonist. In contrast, the current evoked in oocytes transfected with V1a receptor was abolished by the antagonist. Northern blot analysis revealed that the receptor expression is restricted to the pituitary. These data clearly indicate that the cloned cDNA encodes the V1b receptor.
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PMID:Molecular cloning and functional expression of a cDNA encoding the human V1b vasopressin receptor. 792 52

Vasopressin (AVP), the antidiuretic hormone, is a cyclic nonapeptide that acts through binding to G protein-coupled specific membrane receptors pharmacologically divided into three subtypes (V1a, V1b, and V2) linked to distinct second messengers. 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. We report here the structure and functional expression of a human V1a AVP receptor complementary DNA isolated from human liver cDNA libraries. Cloning and sequencing of a full-length clone isolated a 1472-nucleotide sequence encoding a 418-amino acid polypeptide with seven putative transmembrane domains typical of G protein-coupled receptors. Amino acid sequence identity with the rat liver V1a AVP receptor, the human and rat V2 AVP receptors, and the human oxytocin receptor was 72, 36, 37, and 45%, respectively. Functional characterization of the cloned receptor was done by transient expression in COS-7 cells and stable expression in Chinese hamster ovary cells. Localization of the expressed receptor at the cellular surface was illustrated by using the fluorescent linear analog phenylacetyl-D-Tyr(Et)-Phe-Gln-Asn-Lys-Pro-Arg-NH2 coupled to fluorescein-avidin by dodecabiotin. Competition binding experiments with phenylacetyl-D-Tyr(Et)-Phe-Val-Asn-Lys-Pro-[125I]Tyr-NH2 and AVP analogs revealed high affinity specific binding sites of the V1a subtype. Saturation binding experiments with [3H]AVP confirmed the presence of a single class of high affinity binding sites. Measurement of AVP-induced inositol phosphate production and calcium mobilization confirmed that the expressed V1a AVP receptor is coupled to phospholipase C via a pertussis toxin-insensitive pathway. Thus, the human V1a AVP receptor belongs to the superfamily of seven-transmembrane segment receptors with a significant sequence identity with the other members of the AVP-oxytocin family of receptors.
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PMID:Molecular cloning, sequencing, and functional expression of a cDNA encoding the human V1a vasopressin receptor. 810 69

The gene for the bovine oxytocin receptor has been sequenced using a combination of clones derived from a bovine endometrial cDNA library from estrus and a bovine genomic DNA library, with confirmation of structure using reverse transcription PCR programmed by term myometrial RNA. The receptor belongs to the seven transmembrane domain family and predicts a protein of 391 amino acids. A comparison of the genomic sequence with the cDNA structure, as well as reverse transcription polymerase chain reaction (RT-PCR) analysis, shows there are two introns, one in the 5'noncoding region that appears to be differentially spliced in the bovine uterus and a conserved intron within the open reading frame between the regions encoding the transmembrane domains VI and VII. Northern blot analysis indicated three major transcripts in myometrium and endometrium in vivo at approximately 6.5 kb, 3.5 kb, and 2.0 kb. In situ hybridization analysis of uterine tissue at term showed highest mRNA concentrations in the endometrial epithelium, particularly in the deep glands, a pattern confirmed also at the immunohistochemical level by monoclonal antibodies raised against a human amino-terminal peptide. Further confirmation of the identity of the receptor was obtained by transient transfection of a reconstituted receptor construct into COS-7 cells. The expressed receptor was shown to have identical pharmacological properties in respect to various oxytocin analogs to the natural bovine endometrial receptor.
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PMID:Structure and expression of the bovine oxytocin receptor gene. 853 70

The inhibitory activities of acyclovir (ACV), 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU), ganciclovir (GCV), 9-(2-deoxy-2-hydroxymethyl-beta-D-erythro-oxetanosyl)guanine (OXT-G), and (+)-9-[(1R,2R,3S)-2,3-bis(hydroxymethyl)Cyclobutyl]guanine (cOXT-G) on the replication of wild-type and thymidine kinase (TK)-negative strains of herpes simplex virus types 1 and 2 and varicella-zoster virus (VZV) and the wild-type strain of human cytomegalovirus were tested to clarity whether the phosphorylation of these compounds is catalyzed by viral TK or other enzymes. ACV and BV-araU had little effect on the replication of TK-negative virus strains. On the other hand, GCV, OXT-G, and cOXT-G inhibited the replication of TK-negative VZV at concentrations 10 times higher than those at which they inhibited wild-type VZV, indicating that a kinase other than TK phosphorylates GCV and OXT-G in VZV-infected cells. GCV phosphorylation activity was not detected in VZV-infected cell lysates; therefore, this activity was evaluated in COS 1 cells expressing viral TK and viral protein kinase (PK). The COS 1 cells expressing VZV TK were shown to be susceptible to all compounds tested. In contrast, VZV Pk-expressing COS 1 cells were susceptible to only GCV, OXT-G, and cOXT-G. These results suggest that VZV PK phosphorylates some nucleoside analogs, for example, GCV, OXT-G, and cOXT-G. This phosphorylation pathway may be important in the anti-VZV activities of some nucleoside analogs.
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PMID:Analysis of phosphorylation pathways of antiherpesvirus nucleosides by varicella-zoster virus-specific enzymes. 884 52

Defects in peptide processing are associated with several disorders, including central diabetes insipidus (CDI). In the Brattleboro (BB) rat with CDI, the mRNA and protein of arginine vasopressin (AVP) are present in the hypothalamus, but no circulating AVP is detectable, thus suggesting a processing defect. The present study examined AVP secretion in cultured COS cells transfected with various constructs from wild-type and mutated Brattleboro AVP gene precursors. The precursor contains three exons encoding for vasopressin (VP), neurophysin (NP), and glycopeptide (GP). The Brattleboro rat has a deletion of a single base, guanine (G), in the NP coding region that leads to a frameshift, resulting in the loss of normal stop codon. The wild-type pcVP (22.0 +/- 5.2 pg/10[-2] U beta-galactosidase [beta-gal]), but not the mutated BB AVP gene pcBB (1.2 +/- 0.4 pg/10[-2] U beta-gal), was associated with AVP secretion from the COS cells as measured by RIA. The wild-type AVP gene without the GP coding region was associated with AVP release greater (47.4 +/- 13.5 pg/10[-2] U beta-gal, n = 5, P < 0.05, versus pcVP) than the pcVP with intact VP, NP, and GP coding regions. However, the wild-type AVP gene with VP coding region alone was not processed and secreted. Normalizing the pcBB total length with the insertion of a stop codon at the site of the normal stop codon was not associated with AVP secretion (3.0 +/- 1.4 pg/10[-2] U beta-gal). However, insertion of a stop codon so that the pcBB length equaled the length of VP and NP coding regions of the wild type was associated with AVP secretion (13.5 +/- 4.0 pg/10[-2] U beta-gal). When a stop codon was inserted into the wild-type NP coding region at the same site as the G deletion in the pcBB, the AVP secretion was significantly lower (15.1 +/- 5.0 pg/10[-2] U beta-gal) than pcVP with VP + NP but no GP coding regions (47.4 +/- 13.5 pg/10[-2] U beta-gal, n = 5, P < 0.05). In summary, (1) both VP and intact NP, but not GP, coding regions are necessary for AVP processing and secretion; (2) decreasing the length of the NP coding region diminishes but does not abolish AVP processing and secretion; and (3) shortening of the pcBB length with a stop codon at a site comparable to wild-type VP + NP allows AVP secretion, albeit less than with wild-type gene precursor. Thus, the CDI in BB rats is caused by the G deletion in NP coding region. This defect leads to abnormalities that contribute to the abnormal AVP processing. Specifically, the frameshift and absence of a stop codon cause a mutated extended C terminus, which, along with the mutated NP, contribute to the abnormal steps of AVP processing, transport, and secretion in the BB rat. These defects no doubt impair the folding and configuration necessary for normal processing of the AVP gene precursor.
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PMID:Arginine vasopressin secretion with mutants of wild-type and Brattleboro rats AVP gene. 940 88

The effects of cAMP on the oxytocin-stimulated increase in phosphatidylinositide turnover and the possible pathways involved were investigated in a human myometrial cell line (PHM1-41) and in COS-M6 cells overexpressing the oxytocin receptor. Preincubation with chlorophenylthio-cAMP (CPT-cAMP), forskolin, or relaxin inhibited oxytocin-stimulated phosphatidylinositide turnover in PHM1-41 cells, and the inhibition was reversed by H-89, a relatively specific protein kinase A inhibitor. Both CPT-cAMP and transiently expressed protein kinase A catalytic subunit inhibited stimulation by oxytocin and carbachol of [3H]inositol 1,3,4-trisphosphate formation in COS-M6 cells expressing oxytocin or muscarinic M1 receptors, respectively. CPT-cAMP also inhibited phosphatidylinositide turnover stimulation by endothelin-1 in PHM1-41 cells, further demonstrating the generality of the cAMP-inhibitory mechanism. Since G betagamma activation of phospholipase Cbeta2 (PLCbeta2) is a suggested target of protein kinase A, the possibility that the oxytocin receptor couples to PLCbeta2 via G alpha(i)G betagamma activation was explored. Western blot analysis of PHM1-41 cells and COS-M6 cells detected PLCbeta1 and PLCbeta3, but not PLCbeta2. In PHM1-41 cells, pertussis toxin reduced the oxytocin-stimulated increase in [3H]inositol 1,3,4-trisphosphate by 53%, and this was reversed completely by H-89. Thus, the inhibitory effect of pertussis toxin may result from an indirect effect of cAMP elevation. These data suggest that receptor/G alpha(q)-coupled stimulation of PLCbeta1 or PLCbeta3 can be inhibited by cAMP through a phosphorylation mechanism involving protein kinase A that does not involve PLCbeta2. In smooth muscle, this mechanism could constitute potentially important cross-talk between pathways regulating contraction and relaxation.
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PMID:Evidence for inhibition by protein kinase A of receptor/G alpha(q)/phospholipase C (PLC) coupling by a mechanism not involving PLCbeta2. 956 32

The arginine vasopressin (AVP) precursor gene of mammals contains three exons encoding the principal domains of the polyprotein precursor, including vasopressin (exon A), neurophysin (exon B), and glycopeptide (exon C). The AVP precursor (preprohormone) is processed and transported through the endoplasmic reticulum (ER), Golgi apparatus, and secretory vesicles, and finally, mature AVP is secreted from the posterior pituitary into the circulation. The exact steps of these processes during AVP translation and posttranslation events are not yet well elucidated. Defects in peptide processing are associated with several genetic disorders, including central diabetes insipidus (CDI). In the Brattleboro rat with CDI, the mRNA and protein of AVP are present in the hypothalamus, but no circulating AVP is detectable, thus suggesting a processing defect, transport defect, or both. The mutated AVP gene precursor of Brattleboro rat has a deletion of a single base, guanine, in the neurophysin coding region that leads to a frameshift resulting in the loss of the normal stop codon. It has been reported that the mutated precursor is trapped in the ER and does not reach the Golgi apparatus. Recent studies examined AVP secretion in cultured COS cells transfected with various constructs from wild-type and mutated Brattleboro AVP gene precursors. The wild-type in vitro studies demonstrated that intact neurophysin, but not the glycoprotein coding region, is necessary for normal AVP processing and secretion. Next, the results demonstrated that the guanine defect in the neurophysin coding region and the prolonged C-terminus accounted for the processing defect in the Brattleboro rat with CDI. These defects no doubt impair the folding and configuration necessary for normal processing of the AVP gene precursor in the ER. In hereditary CDI in humans, the majority of the mutations have also been shown to occur in the neurophysin coding region. However, in contrast to the recessive defect in the Brattleboro rat, in human CDI, neurotoxicity and denigration of the magnocellular neurons have been observed, and dominant inheritance occurs. Moreover, all mutations are missense, nonsense, or deletions in human CDI rather than the shift in reading frame and preserved neurons that is observed with the Brattleboro rat. Thus, the results from studies in the Brattleboro rat may only be partially applicable to hereditary CDI in humans.
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PMID:Vasopressin processing defects in the Brattleboro rat: implications for hereditary central diabetes insipidus in humans? 975 87

Oxytocin stimulates an increase in intracellular calcium in uterine myometrium by several mechanisms. Several lines of evidence indicate that the oxytocin receptor is functionally coupled to GTP-binding proteins of the G alpha q/11 class which stimulate phospholipase C activity. The IP3 generated as a result of phospholipase C activation can trigger release of calcium from intracellular stores. The finding that the oxytocin-stimulated increase in intracellular calcium in myometrial cells is greater in the presence of extracellular calcium than that in its absence indicates that oxytocin also has effects on calcium entry. This action is nifedipine-insensitive but may involve indirect stimulation of calcium entry through release-operated channels. An anti-G alpha q/11 antibody inhibits both oxytocin-stimulated GTPase activity and phospholipase C activity in myometrial membranes. The stimulation by oxytocin of phosphoinositide turnover in COS cells transfected with a plasmid expressing the oxytocin receptor is enhanced by cotransfection of G alpha q. Co-transfection of intracellular domains of the oxytocin receptor causes varying degrees of interference with oxytocin-stimulated phosphoinositide turnover. The data suggest that more than one intracellular domain is involved in oxytocin receptor/G-protein coupling. Oxytocin receptor stimulation of phospholipase C is inhibited by cAMP. This occurs in myometrial cells and in COS cells transfected with a plasmid expressing the receptor. The inhibitory mechanism involves the action of protein kinase A and is probably targeted indirectly at the G alpha q/11 /phospholipase C coupling step.
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PMID:Molecular mechanisms regulating the effects of oxytocin on myometrial intracellular calcium. 1002 15

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