Inhibition by (D-Trp12,Tyr34)bPTH(7-34)amide of PTH and PTHrP effects on Pi transport in renal cells.
We studied the effect of (D-Trp12,Tyr34)bovine parathyroid hormone-(7-34)amide [(D-Trp12,Tyr34)bPTH(7-34)NH2], a recently described highly potent antagonist of parathyroid hormone (PTH), on the adenosine 3',5'-cyclic monophosphate (cAMP) and the sodium-dependent phosphate transport (NaPiT) responses to bPTH-(1-34) or PTH-related protein [PTHrP(1-34)] in renal epithelial cells. In this system, bPTH and PTHrP increased cAMP production and inhibited NaPiT in a similar manner. (D-Trp12,Tyr34)bPTH(7-34)NH2 did not influence either cAMP or NaPiT, but markedly attenuated the responses to PTH or PTHrP. The effect was concentration dependent, and a maximal inhibition of PTH or PTHrP effects was obtained with a 10(3)- to 10(4)-fold greater concentration of the antagonist. In contrast, the same concentration of the unsubstituted counterpart, (Tyr34)bPTH(7-34)NH2, which abolished the PTH- or PTHrP-induced stimulation of cAMP production, did not affect the inhibition of NaPiT caused by either peptide. Thus (D-Trp12,Tyr34)bPTH(7-34)NH2 inhibited the effects of PTH and PTHrP on both cAMP synthesis and Pi transport in renal cells. Because of the effects of this analogue on a transport function affected by these two peptides under physiological and pathophysiological conditions, it appears to be a promising antagonist.
Pizurki
L
L
Department of Medicine, University Hospital of Geneva, Switzerland.
Rizzoli
R
R
Bonjour
J P
JP
D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis; D007668:Kidney / Q000166:cytology / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000494:pharmacology*; D010710:Phosphates / Q000378:metabolism*; D011506:Proteins / Q000494:pharmacology*; D012964:Sodium / Q000494:pharmacology
D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D010710:Phosphates; D011506:Proteins; C054296:parathyroid hormone-related protein (1-34); C057402:parathyroid hormone (7-34)amide,12-Trp,34-Tyr-, bovine; D012964:Sodium; D000242:Cyclic AMP