EndothelinB receptor activation enhances parathyroid hormone-induced calcium signals in UMR-106 cells.
In studies of the regulation of parathyroid hormone (PTH) signal transduction, we observed that the peptide endothelin-1 (ET) added prior to PTH greatly increased the calcium transients elicited by PTH in UMR-106 osteosarcoma cells and mouse primary osteoblastic cells. Enhancement by ET also occurred in the presence of EGTA. The ETB receptor-specific agonist sarafotoxin 6c (S6c) likewise enhanced PTH-induced Ca2+ transients. Blocking the ETA receptor-mediated component of the ET signal with BQ123 failed to abolish enhancement of PTH responses by ET. The nonselective ETA/ETB receptor antagonist PD 142893 blocked both ET and S6c-induced enhancement of the PTH responses. Prostaglandin F1 alpha (PGF1 alpha) pretreatment also maximally potentiated PTH responses, whereas alpha-thrombin, epidermal growth factor (EGF), or prostaglandin E1 (PGE1) did not affect the PTH responses. Neither active phorbol ester nor forskolin mimicked the ET effect. The ET effect was not prevented by indomethacin, NG-mono-methylarginine, genistein, pertussis toxin, 4-aminopyridine, tetraethylammonium chloride, okadaic acid, or long-term treatment with phorbol-12,13-dibutyrate. ET pretreatment did not abolish the inhibition of PTH signals by PTH(3-34), although in ET-pretreated cells the suppression of the PTH signal by PTH(3-34) was not as great. ET pretreatment did not enhance the cAMP response to PTH; rather, there was a significant inhibition of the cAMP response. Thus, the calcium signal elicited by PTH is selectively modulated by activation of the ETB receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Lee
S K
SK
Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois, USA.
Stern
P H
PH
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004357:Drug Synergism; D016232:Endothelins / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects*; D013917:Thrombin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016232:Endothelins; D010281:Parathyroid Hormone; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D004815:Epidermal Growth Factor; D013917:Thrombin; D002118:Calcium