Human Myometrium during Pregnancy Contains and Responds to VI Vasopressin Receptors as well as Oxytocin Receptors*

Maggi, Mario; Carlo, Paola Del; Fantoni, Guido; Giannini, Stefano; Torrisi, Cristina; Casparis, D; Massi, Giambattista; Serio, Mario

doi:10.1210/jcem-70-4-1142

Cited by 114 publications

(71 citation statements)

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“…In humans, oxytocin acts on the oxytocin and vasopressin receptors and is one of the key players in the induction of labor and uterine contraction (20). Oxytocin and V 1a receptors are both expressed in the pregnant human uterus and are up-regulated during parturition, making the tissue more sensitive for stimulation (26). The endogenous ligand oxytocin is used clinically to induce labor and to prevent life-threatening postpartum bleeding (20).…”

Section: Discussionmentioning

confidence: 99%

Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design

Koehbach

O’Brien

Muttenthaler

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

140

161

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Cyclotides are plant peptides comprising a circular backbone and three conserved disulfide bonds that confer them with exceptional stability. They were originally discovered in Oldenlandia affinis based on their use in traditional African medicine to accelerate labor. Recently, cyclotides have been identified in numerous plant species of the coffee, violet, cucurbit, pea, potato, and grass families. Their unique structural topology, high stability, and tolerance to sequence variation make them promising templates for the development of peptide-based pharmaceuticals. However, the mechanisms underlying their biological activities remain largely unknown; specifically, a receptor for a native cyclotide has not been reported hitherto. Using bioactivity-guided fractionation of an herbal peptide extract known to indigenous healers as "kalatakalata," the cyclotide kalata B7 was found to induce strong contractility on human uterine smooth muscle cells. Radioligand displacement and second messenger-based reporter assays confirmed the oxytocin and vasopressin V 1a receptors, members of the G proteincoupled receptor family, as molecular targets for this cyclotide. Furthermore, we show that cyclotides can serve as templates for the design of selective G protein-coupled receptor ligands by generating an oxytocin-like peptide with nanomolar affinity. This nonapeptide elicited dose-dependent contractions on human myometrium. These observations provide a proof of concept for the development of cyclotide-based peptide ligands.yclotides are head-to-tail cyclized plant peptides containing three conserved disulfide bonds in a knotted arrangement known as a cyclic cystine-knot motif (1). This confers them high stability (2) and presumably improves their oral bioactivity relative to their linear counterparts (3). They were first discovered in a decoction of Oldenlandia affinis DC. (Rubiaceae) leaves, an herbal remedy used in traditional African medicine during childbirth (4). The observed induction of labor and shortened delivery time were later studied on isolated rat and rabbit uteri and on human uterine strips (4, 5). The peptides responsible for the contractility effects (5) raised interest because they survived boiling, presumably as a result of their unique 3D structure, which was elucidated in 1995 (6). Since then, several plant species of the coffee (Rubiaceae) (7), violet (Violaceae) (8), legume (Fabaceae) (9), potato (Solanaceae) (10) and grass (Poaceae) families (11) have been identified to produce cyclotides. Currently, ∼300 sequences have been reported (12), and the predicted number of >50,000 cyclotides in Rubiaceae alone (7) suggests them to be one of the largest peptide classes within the plant kingdom. Their high intercysteine sequence variability and structural plasticity (13), together with intrinsic bioactivities, make them interesting templates for the development of novel pharmaceuticals (14).However, five decades after the discovery of cyclotides, there still is not any information about specific molecular targe...

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Section: Discussionmentioning

confidence: 99%

Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design

Koehbach

O’Brien

Muttenthaler

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

140

161

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“…AVP has been suggested to have a physiological role in the myometrium as it can induce uterine contractions [78], and similar with OTR regulation, there are some studies that suggest increase in the density of V1aR during the later weeks of gestation and in preterm labour tissues [79,80]. Therefore it may be hypothesized that OTR/V 1a R or OTR/V 2 R dimers have a functional role in the onset of labour.…”

Section: Otr/avprmentioning

confidence: 96%

Advances in the role of oxytocin receptors in human parturition

Kim

Bennett

Terzidou

2017

Molecular and Cellular Endocrinology

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“…In turn, the rise in intracellular calcium concentration promotes a cascade of events, including phosphorylation of myosin, that then acts on actin and induces uterine muscle cell contraction. Before onset of labor and in the term myometrium, the OT-R density increases dramatically (Fuchs et al, 1982;Maggi et al, 1990). The onset of labor is not associated with an increase in levels of circulating OT and, therefore, the exact role of OT remains controversial.…”

mentioning

confidence: 99%

Pharmacology of (2S,4Z)-N-[(2S)-2-Hydroxy-2-phenylethyl]-4-(methoxyimino) -1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide, a New Potent and Selective Nonpeptide Antagonist of the Oxytocin Receptor

Cirillo¹,

Tos²,

Schwarz³

et al. 2003

J Pharmacol Exp Ther

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We have discovered a new, potent, selective, and orally active oxytocin receptor antagonist, (2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2Ј-methyl[1,1Ј-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (compound 1).We report the biochemical, pharmacological, and pharmacokinetic characterization in vitro and in vivo of this compound. Premature birth is a major problem in obstetrics affecting about 10% of all births and being the largest cause of perinatal morbidity and mortality. The impact on society is significant in terms of costs of neonatal intensive care and for the emotional and social stress to the family. The physiopathology of human preterm labor is complex and multifactorial. Preterm increase of uterine activity is a common complication of pregnancy and accounts for many cases of preterm labor. Pharmacological interventions aimed at maintaining uterine quiescence (tocolysis) have been, and are likely to remain, the cornerstone of pharmaceutical management of preterm labor. However, current tocolytic agents (␤-mimetics, magnesium sulfate, calcium channel blockers, or prostaglandin synthesis inhibitors) suffer from a minimal effectiveness and show important fetal and maternal side effects. Therefore, it is obvious that a safe and effective oral treatment delaying spontaneous preterm birth would have tremendous clinical benefits.The peptide hormone oxytocin (OT) is a potent contractor of the human uterus. OT mediates its effect through activation of the G protein-coupled oxytocin receptor (OT-R) that is expressed in myometrial cells. OT-R is coupled to phospholipase C activation, leading to intracellular synthesis of inositol phosphates and mobilization of calcium. In turn, the rise in intracellular calcium concentration promotes a cascade of events, including phosphorylation of myosin, that then acts on actin and induces uterine muscle cell contraction. Before onset of labor and in the term myometrium, the OT-R density Article, publication date, and citation information can be found at

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Human Myometrium during Pregnancy Contains and Responds to VI Vasopressin Receptors as well as Oxytocin Receptors*

Cited by 114 publications

References 0 publications

Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design

Oxytocic plant cyclotides as templates for peptide G protein-coupled receptor ligand design

Advances in the role of oxytocin receptors in human parturition

Pharmacology of (2S,4Z)-N-[(2S)-2-Hydroxy-2-phenylethyl]-4-(methoxyimino) -1-[(2′-methyl[1,1′-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide, a New Potent and Selective Nonpeptide Antagonist of the Oxytocin Receptor

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