Studies of structure-function relationship of human parathyroid hormone using rat and human renal cortical cells in...

The structure-function relationship of human PTH was studied by testing the effects of its synthetic analogues on cAMP production in cultures of rat and human renal cortical cells. The human cell system was by two orders more sensitive to an agonist, hPTH1-34, than the rat cell system. In both culture systems, Tyr34hPTH3-34NH2, which by itself had no influence on adenylate cyclase, caused approximately 90% inhibition of the hPTH 1-34-induced cAMP production at a molar ratio of 1000:1. On the other hand, Tyr34hPTH5-34NH2, Tyr34hPTH7-34NH2, Tyr34hPTH8-34NH2 and Tyr34hPTH9-34NH2 had weak but distinct agonist activity. When these four analogues were tested in the presence of hPTH1-34, they acted as antagonists in the human cell system, whereas they still showed agonist activity in the rat cell system which was additive to that of hPTH1-34. These data indicate that the amino acids at positions 1 and 2 of hPTH are important for its biological activity and that those in the sequence 9-34 also participate in the activation of adenylate cyclase. The higher sensitivity to hPTH1-34 and the different response to some of the analogues of human renal cortical cells compared with rat renal cortical cells emphasize the importance of employing human cell systems in evaluating the structure-function relationship of hPTH.