ACTIVITY OF CAMP-DEPENDENT PROTEIN-KINASE IS REDUCED IN PROTEIN-ENERGY MALNOURISHED RATS

Glucagon decreases glutathione synthesis in hepatocytes from well-nour ished rats. However, in hepatocytes from malnourished rats, glucagon d oes 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 r ats 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 rece ptor and forskolin-stimulated cAMP production were greater in hepatocy tes from malnourished rats. Stimulation of adenylyl cyclase with forsk olin, guanine nucleotides or manganese in hepatic membranes was also e nhanced after malnutrition. Moreover, quantity of the stimulatory guan ine nucleotide regulatory protein was 70-80% greater in hepatocytes fr om malnourished rats but the inhibitory guanine nucleotide regulatory protein was not different. These results suggested that desensitizatio n of cAMP-mediated signal transduction after malnutrition occurred at a site distal to cAMP production. Maximal activity of cAMP-dependent p rotein kinase was 60% lower in liver homogenates from malnourished rat s 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 kin ase in the cytosol of malnourished rats was associated with a 43% redu ction in the quantity of regulatory subunit type I, with no difference in the regulatory subunit type II. These data indicate that desensiti zation of cAMP signal transduction in rat liver after malnutrition is due to a decrease in the quantity and activity of cAMP dependent prote in kinase.