Contractile actions of thrombin receptor-derived polypeptides in human umbilical and placental vasculature: evidence for distinct receptor systems.
1. We studied the structure-activity profiles of four thrombin receptor-derived polypeptides (TRPs) (P5, SFLLR; P5-NH2, SFLLR-NH2; P7, SFLLRNP; P7-NH2, SFLLRN) in contractile human placental artery (PA), umbilical artery (UA) and umbilical vein (UV) preparations and in a human platelet aggregation assay. 2. The contractile actions of the TRPs in the two arterial preparations were endothelium-independent, whereas in the UV tissue a contractile response was observed only in an endothelium-denuded preparation; no endothelium-mediated relaxation responses were observed in any of the vascular preparations. 3. In the three vascular preparations, the contractile responses required extracellular calcium and were attenuated by the tyrosine kinase inhibitor, genistein. 4. The relative contractile orders of potencies of the TRPs in the three vascular preparations were distinct from each other (PA: P7-NH2 > P7 > P5-NH2 > P5; UA: P7-NH2 > or = P5-NH2 approximately = P7 > > P5; UV: P5-NH2 > > P7-NH2 = P7 > > P5) and these were in turn distinct from the potency order observed in the platelet aggregation assay (P5-NH2 > or = P7-NH2 > P7 > > P5). 5. Despite the markedly dissimilar TRP potency orders in the placental artery and umbilical vein preparations, the cDNA sequences for the thrombin receptor obtained by polymerase chain reaction cloning of cDNA from the two tissue sources were identical. 6. We conclude that the four tissues studied possess functionally distinct thrombin receptor systems that interact in a distinct way with agonist peptides. In view of the identity of the thrombin receptor cDNA in the two tissues displaying the most dissimilar structure-activity profiles, we suggest that in different tissues, differences in post-translational receptor processing or differences in receptor-effector coupling interactions may result in unique thrombin receptor systems that can display distinct structure-activity profiles.
Tay-Uyboco
J
J
Department of Pharmacology & Therapeutics, University of Calgary, Faculty of Medicine, Canada.
Poon
M C
MC
Ahmad
S
S
Hollenberg
M D
MD
D000595:Amino Acid Sequence; D001158:Arteries / Q000187:drug effects; D001483:Base Sequence; D002118:Calcium / Q000494:pharmacology / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers / Q000737:chemistry; D018076:DNA, Complementary / Q000737:chemistry / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010920:Placenta / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D018179:Receptors, Thrombin / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000494:pharmacology; D014469:Umbilical Arteries / Q000187:drug effects* / Q000378:metabolism; D014471:Umbilical Veins / Q000187:drug effects* / Q000378:metabolism
D017931:DNA Primers; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D010455:Peptides; D018179:Receptors, Thrombin; D013917:Thrombin; D002118:Calcium