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Activity of cAMP-Dependent Protein Kinase is Reduced in Protein-Energy Malnourished Rats^1,2,3,

Department of Nutritional Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada

Glucagon decreases glutathione synthesis in hepatocytes from well-nourished rats. However, in hepatocytes from malnourished rats, glucagon does not inhibit glutathione synthesis, suggesting a desensitization of cAMP-mediated signal transduction. We investigated the mechanism for this desensitization of cAMP-mediated responsiveness in malnourished rats by comparing the signal transduction pathways in rats fed very low protein diets (0.5 g protein/100 g diet) with those of rats fed diets adequate in protein (15 g protein/100 g diet) for 2 wk. Glucagon receptor and forskolin-stimulated cAMP production were greater in hepatocytes from malnourished rats. Stimulation of adenylyl cyclase with forskolin, guanine nucleotides or manganese in hepatic membranes was also enhanced after malnutrition. Moreover, quantity of the stimulatory guanine nucleotide regulatory protein was 70–80% greater in hepatocytes from malnourished rats but the inhibitory guanine nucleotide regulatory protein was not different. These results suggested that desensitization of cAMP-mediated signal transduction after malnutrition occurred at a site distal to cAMP production. Maximal activity of cAMP-dependent protein kinase was 60% lower in liver homogenates from malnourished rats compared with controls. This difference in activity was confined to the cytosolic compartment, with no difference in activity observed in the particulate fraction. Lower activity of cAMP-dependent protein kinase in the cytosol of malnourished rats was associated with a 43% reduction in the quantity of regulatory subunit type I, with no difference in the regulatory subunit type II. These data indicate that desensitization of cAMP signal transduction in rat liver after malnutrition is due to a decrease in the quantity and activity of cAMP-dependent protein kinase.

KEY WORDS: • guanine nucleotide regulatory proteins • glutathione • hepatocytes • rats • malnutrition

¹ Presented in part at the annual meeting of the Canadian Federation of Biological Sciences, June 17–19, 1993, Windsor, Ontario, Canada [Nagy, L. E., Goss, P. M. & Bray, T. M. (1993) cAMP signal transduction in protein energy malnutrition. Can. Fed. Biol. Sci. 36:129 (abs.)].

² Supported in part by grants from ILSI North America (L.E.N.) and NSERC (T.M.B.).

³ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

⁴ To whom correspondence should be addressed.

Manuscript received 6 May 1994. Revision accepted 10 August 1994.