GRP-preferring bombesin receptors increase generation of inositol phosphates and tension in rat myometrium.
In the estrogen-treated rat myometrium, bombesin (Bn) and related agonists triggered contraction and the increased generation of inositol phosphates. The relative order of potencies was identical for both responses: Bn = gastrin releasing peptide (GRP) = litorin = neuromedin C >> neuromedin B. Two specific GRP-preferring receptor antagonists, namely [D-Phe6]Bn-(6-13) methyl ester and [Leu14,psi 13-14]Bn were inhibitory for both Bn-mediated tension and generation of inositol phosphates. [125I-Tyr4]Bn bound to myometrial membranes with high affinity (Kd = 104 pM) to a single class of sites in a saturable and reversible manner. The relative potencies for inhibiting binding were GRP = litorin = [Tyr4]Bn (Ki = 0.4 to 0.6 nM) >> neuromedin B (Ki = 10.3 nM). The high affinity displayed by [D-Phe6]Bn-(6-13) methyl ester (Ki = 2.8 nM) and [Leu14,psi 13-14]Bn (Ki = 35 nM) for competing for [Tyr4]Bn binding supported the involvement of a GRP-preferring Bn receptor. Guanine nucleotides decreased the binding of [125I-Tyr4]Bn and accelerated the rate of ligand dissociation, reflecting the coupling of receptors to guanine nucleotide regulatory proteins (G proteins). The results demonstrate that rat myometrium expresses functional GRP-preferring Bn receptors whose activation stimulates the phospholipase C pathway, pertussis toxin-insensitive event that contributes to Bn-mediated uterine contractions.
Amiot
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F
Laboratoire d'Endocrinologie et Régulations Cellulaires, Centre National de la Recherche Scientifique, Unité de Recherche Associée 1131, Université Paris Sud, Orsay, France.
Leiber
D
D
Marc
S
S
Harbon
S
S
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001839:Bombesin / Q000378:metabolism / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D019886:Gastrin-Releasing Peptide; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000302:isolation & purification / Q000378:metabolism; D007700:Kinetics; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009215:Myometrium / Q000187:drug effects / Q000502:physiology*; D015287:Neurokinin B / Q000031:analogs & derivatives / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D037342:Pertussis Toxin; D051381:Rats; D017208:Rats, Wistar; D018004:Receptors, Bombesin / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014590:Uterine Contraction / Q000187:drug effects*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D007295:Inositol Phosphates; D009842:Oligopeptides; D010446:Peptide Fragments; D010455:Peptides; D018004:Receptors, Bombesin; D010566:Virulence Factors, Bordetella; D006165:Guanylyl Imidodiphosphate; C022571:adenosine 5'-O-(3-thiotriphosphate); D016244:Guanosine 5'-O-(3-Thiotriphosphate); C010212:litorin; D019886:Gastrin-Releasing Peptide; C040794:neuromedin C; D015287:Neurokinin B; C038393:neuromedin B; D000255:Adenosine Triphosphate; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D001839:Bombesin