Endothelin receptor type A signals both the accumulation of inositol phosphates and the inhibition of cyclic AMP generation in rat myometrium: stimulation and desensitization.
In estradiol-dominated rat myometrium, endothelin (ET)-1 caused contraction and increased the accumulation of [3H]inositol phosphates (EC50 = 70 nM), with the sequential generation of inositol trisphosphate, inositol bisphosphate, and inositol monophosphate. There was a coincident early decrease in phosphatidyl-inositol bisphosphate. The ET-1 stimulatory effect was pertussis toxin insensitive, suggesting an activation of phospholipase C via Gq/G11 proteins. ET-1 also inhibited the generation of cAMP induced by forskolin (EC50 = 30 nM). The inhibition was maintained in Ca(2+)-depleted medium and was prevented by pertussis toxin, suggesting G(i)-mediated inhibition of adenylyl cyclase. The rank order of potency for these various ET-1 effects [ET-1 > (Thr2)-sarafotoxin-b >> ET-3], as well as the inhibitory effect displayed by BQ123, a specific ETA receptor antagonist, provided evidence for the involvement of the ETA receptor subtype. Exposure to ET-1 (15 min) resulted in concentration-dependent and homologous desensitization (40%) of the inositol phosphate response triggered by ET-1. There was virtually no recovery of ET-1-mediated inositol phosphate responses in the desensitized tissue even after 180 min of incubation. In contrast, the persistent low level of ET-1 activity that was observed in spite of several washings and in the absence of rechallenge with ET-1 was progressively revsersed and totally eliminated by BQ123. The ET-1 inhibitory effect on cAMP was also desensitized, as evidenced by the attenuation of the inhibitory effect of ET-1 after 15 min of ET-1 pretreatment. The data indicate that in rat myometrium the ETA receptor is coupled, via two distinct G proteins, to two main signal transduction cascades, which both undergo rapid desensitization.
Khac
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CNRS URA 1131, Bt 432 Université Paris Sud, Orsay, France.
Naze
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Harbon
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D037361:Adenylate Cyclase Toxin; D000818:Animals; D000242:Cyclic AMP / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology; D005260:Female; D007295:Inositol Phosphates / Q000378:metabolism*; D009215:Myometrium / Q000187:drug effects / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000494:pharmacology; D037342:Pertussis Toxin; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D014590:Uterine Contraction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007295:Inositol Phosphates; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; D010566:Virulence Factors, Bordetella; C057354:sarafotoxins s6; D000242:Cyclic AMP; D037342:Pertussis Toxin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)