Short-term feedback regulation of cAMP by accelerated degradation in rat tissues

T. W. Gettys, P. F. Blackmore, J. B. Redmon, S. J. Beebe, J. D. Corbin

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A recent study showed that cAMP analogs lowered cAMP levels in rat hepatocytes. The present work demonstrates that cAMP analogs also lowered cAMP in a rapid, concentration-dependent manner in heart and fat cells. In order to determine if the cAMP-dependent protein kinase mediated this effect, techniques were developed to assay the protein kinase activity ratio in hepatocytes treated with cAMP analogs. The activation of protein kinase and phosphorylase in hepatocytes by 8-pClΦS-cAMP (where 8-pClΦS- indicates 8-parachlorothiophenyl-) was concentration-dependent and occurred in parallel to proportionate decreases in cAMP. More than 20% of the cAMP binding sites on the protein kinase were unoccupied at concentrations of 8-pClΦS-cAMP that produced maximal cAMP lowering. Thus, the possibility that 8-pClΦS-cAMP lowered cAMP by displacing it from protein kinase binding sites, making it available for hydrolysis, seemed unlikely. In adipocytes, the lowering of cAMP by 8-pClΦS-cAMP occurred in parallel with increases in lipolysis and activation of low K(m) phosphodiesterase, suggesting that the phosphodiesterase was responsible for the cAMP lowering. Further evidence for this assertion was the finding that in hepatocytes preloaded with low concentrations of 8-pClΦS-cAMP, glucagon lowered 8-pClΦS-cAMP by about 50%, an amount similar to the cAMP lowering observed with 8-pClΦS-cAMP treatment. The results were consistent with a cAMP-dependent protein kinase-catalyzed activation of a phosphodiesterase and suggested that 8-pClΦS-cAMP-mediated hydrolysis of cAMP mimicked a physiologically significant response. The observation of this phenomenon in several tissues further suggested that it may a general mechanism for dampening and terminating the hormonal signal through accelerated degradation of cAMP.

Original languageEnglish (US)
Pages (from-to)333-339
Number of pages7
JournalJournal of Biological Chemistry
Issue number1
StatePublished - 1987


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