M. Rozwadowski et al., ACTIVITY OF CAMP-DEPENDENT PROTEIN-KINASE IS REDUCED IN PROTEIN-ENERGY MALNOURISHED RATS, The Journal of nutrition, 125(3), 1995, pp. 401-409
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.