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Endocrinology, Vol 131, 2161-2164, Copyright © 1992 by Endocrine Society

ARTICLES

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

KJ Martin, CJ McConkey Jr and MP Caulfield
Department of Internal Medicine, St. Louis University School of Medicine, Missouri 63110.

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.




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Copyright © 1992 by The Endocrine Society