VERY-LOW PROTEIN DIETS INDUCE A RAPID DECREASE IN HEPATIC CAMP-DEPENDENT PROTEIN-KINASE FOLLOWED BY A SLOWER INCREASE IN ADENYLYL-CYCLASE ACTIVITY IN RATS

Recent evidence indicates that cAMP-mediated responses are desensitize d in liver during malnutrition. While receptor-stimulated production o f cAMP is increased in hepatocytes from rats fed very low protein diet s for 14 d, activity of cAMP-dependent protein kinase (PKA) is decreas ed in liver cytosol. The present study investigated the time course fo r this desensitization. Weanling rats were fed either a 0.5 (malnouris hed) or 15% protein (control) diet for 1, 3, 7 or 14 d. Total PKA acti vity decreased after only 3 d of feeding the low protein diet. This de crease was confined to the cytosolic compartment and was associated wi th a lower quantity of immunoreactive RI regulatory subunit of PKA, wi th no difference in the quantity of immunoreactive RII regulatory subu nit. In contrast, basal-, MnCl2- and guanine nucleotide regulatory pro tein-stimulated adenylyl cyclase activities were not greater in liver membranes of malnourished rats than in those of the control rats until the 2nd wk of feeding. Greater activity was paralleled by an increase in the quantity of the stimulatory guanine nucleotide regulatory prot ein at d 14. The inhibitory guanine nucleotide regulatory protein quan tity did not differ between dietary groups. Greater cAMP production wa s not mediated by changes in PKA phosphorylation of adenylyl cyclase b ecause preincubation of membranes with purified PKA catalytic subunit decreased MnCl2-stimulated cAMP production equally in liver membranes of both control and malnourished rats. Similarly, treatment with alkal ine phosphatase decreased adenylyl cyclase activity but did not elimin ate the difference in adenylyl cyclase activity between control and ma lnourished rats. These data demonstrate that loss of PKA activity is a n early response to a low protein diet and that, subsequently, a numbe r of molecular adaptations occur which increase cAMP production. These changes may be adaptive responses to malnutrition that maintain essen tial cAMP-dependent functions.