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The role of protein kinase-A activity in the evaluation of agonist/antagonist properties of analogs of parathyroid hormone-related protein in opossum kidney cells.

Structural modifications of the amino-terminal region of PTH resulted in the generation of PTH analogs with potent antagonist activities and markedly reduced agonist activities. Further development of these structure-function relationships to modifications of the sequence of the PTH-related protein (PTHrP) resulted in PTH/PTHrP antagonist analogs with increased antagonist activity and little if any agonist effects. Since studies from our laboratory have shown that measurement of protein kinase-A activity appears to be a more sensitive index of the actions of PTH than measurements of total cAMP, the present studies were designed to examine the effects of a series of PTHrP-based peptides for agonist/antagonist effects in opossum kidney (OK) cells. The results show that PTHrP-(7-34)NH2, which does not increase cAMP, displays agonist activity in terms of increasing protein kinase-A activity. Furthermore, [Leu11,D-Trp12]PTHrP-(7-34)NH2 and [D-Trp12]PTHrP-(7-34)NH2, which appear to be effective antagonists of rat PTH-(1-34)-stimulated cAMP generation, were less effective in antagonizing the effects on protein kinase-A and only [Leu11,D-Trp12] PTHrP-(7-34)NH2 appeared to exhibit any antagonist activity. The Ki for [Leu11,D-Trp1/]PTHrP-(7-34)NH2 to antagonize the stimulatory effect of 1 nM rat PTH-(1-34) was easily demonstrable by measurements of cAMP, but could not be demonstrated using the assay of protein kinase-A activity. These data underscore the observation that measurement of protein kinase-A is a more sensitive index of the effects of PTH than measurements of cAMP and that significant agonist activity on the cAMP/protein kinase pathway cannot be excluded without measurements of protein kinase-A activity.