Human PTH-(3-34) inhibited the effects of human parathyroid hormone-related protein on phosphate uptake in a cultured renal cell line (OK cells).
The action mechanism of hPTH and hPTHrP-(1-34) on phosphate uptake in opossum kidney (OK) cells was studied using [Nle8,18Tyr34]hPTH-(3-34)-NH2, a potent competivie inhibitor of adenylate cyclase-coupled PTH receptor. We examined the effects of hPTH-(1-34), hPTHrP-(1-34), and hPTH-(3-34) separately or in combination on the change in renal cyclic AMP production and phosphate uptake in OK cells. Both hPTH-(1-34) and hPTHrP-(1-34) stimulated intracellular cyclic AMP production to the same degree at concentrations between 10(-10) and 10(-7) M and inhibited phosphate uptake equipotently on a molar basis (27.5 +/- 2.0 and 33.2 +/- 1.2% inhibition at 10(-7) M, respectively). Both exogenous addition of (Bu)2cAMP and endogenous stimulation of cAMP by forskolin inhibited phosphate uptake in a dose-dependent manner. Cyclic AMP production induced by either hPTH-(1-34) or hPTHrP-(1-34) was inhibited by both [Nle8,18Tyr34]-hPTH-(3-34)-NH2 and [Tyr34]-hPTH-(7-34)-NH2. However, [Nle8,18Tyr34]hPTH-(3-34)-NH2 and [Tyr34]-hPTH-(7-34)-NH2 inhibited hPTH-induced cAMP production more strongly. The inhibitory action of phosphate uptake by hPTH-(1-34) and hPTHrP-(1-34) was prevented in the presence of a 100-fold greater concentration of [Nle8,18Tyr34]hPTH-(3-34)-NH2. The antagonistic action of [Nle8,18Tyr34]hPTH-(3-34)-NH2 on the inhibition of phosphate uptake induced by hPTH-(1-34) and hPTHrP-(1-34) became weaker with time (0-120 minutes), and [Nle8,18Tyr34]hPTH-(3-34)-NH2 did not antagonize the inhibition of phosphate uptake induced by hPTHrP-(1-34) at 120 minutes of incubation.(ABSTRACT TRUNCATED AT 250 WORDS)
Nakai
M
M
Department of Medicine, Kobe University School of Medicine, Japan.
Fukase
M
M
Yamaguchi
T
T
Tsukamoto
T
T
Fujii
N
N
Fujita
T
T
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002452:Cell Count / Q000187:drug effects; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009893:Opossums; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010710:Phosphates / Q000378:metabolism*; D011506:Proteins / Q000037:antagonists & inhibitors*
D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D010710:Phosphates; D011506:Proteins; C054296:parathyroid hormone-related protein (1-34); D005576:Colforsin; D003994:Bucladesine; C025497:parathyroid hormone (3-34) amide, Nle(8,18)-Nle(34)-; C038040:parathyroid hormone (7-34)amide, Tyr(34)-; D000242:Cyclic AMP