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The interaction of three guanyl nucleotides with parathyroid hormone (PTH)-sensitive adenylyl cyclase in canine renal cortical membranes was assessed. Results seen after mixing various proportions of the naturally occurring nucleotide GTP, and the nucleotide analogs 5′ -guanylylimidodiphosphate (Gpp(NH)p) and 5′ -guanylyl methylene diphosphonate (Gpp(CH2)p) suggest that the compounds share a common locus of action, probably distal to the hormonereceptor interaction. The nucleotide (Gpp(NH)p) exerted a marked influence on a variety of synthetic analogs of PTH, increasing the apparent affinity of all PTH derivatives tested and the intrinsic activity of all partial agonists. Most notably the potency of the NH2- terminal tetratriacontapeptide of bovine PTH (bPTH), which in assays using dog renal membranes is only 20% that of the native hormone, increased to 100% when assayed with the nucleotide, and the hormone analog (desamino-Ala-l)-bPTH-(1–34), shown to be active in vivo but inert in in vitro adenylyl cyclase assays in the absence of the nucleotide, was demonstrated to be a partial agonist in its presence.

The analog bPTH-(1–26), previously found to be inert, was shown to be a partial agonist in the sensitive canine renal adenylyl cyclase assay even in the absence of added nucleotide, but was virtually a full agonist in the presence of added Gpp(NH)p. The results suggest the value of further studies employing the guanyl nucleotide to determine the potential role of GTP in hormone action in vivo and for more effective use of the in vitro adenylyl cyclase assay to examine the potency of hormone analogs.

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Copyright © 1978 by The Endocrine Society
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