Denervation and hyperinnervation in the nervous system of diabetic animals: III. Functional alterations of G proteins in diabetic encephalopathy.
G protein-mediated effects on cAMP production were evaluated in the corpus striatum of diabetic rats 5 and 14 weeks after alloxan injection by measuring both D1-receptor-induced stimulation and D2-receptor-mediated inhibition of adenylate-cyclase activity. At 5 weeks of diabetes, no obvious alterations of G protein functions were detected. Both dopamine-stimulated adenylate cyclase and bromocriptine-induced inhibition of enzyme activity were indeed similar in control and diabetic animals. Fourteen weeks after alloxan injection, profound alterations were observed. Dopamine-stimulated cAMP production was markedly increased in diabetic rats, whereas bromocriptine ability to reduce cAMP formation was almost abolished at this late stage of diabetes. Hypoactivity of Gi/Go proteins was also confirmed by the reduced ability of the GTP non-hydrolyzable analog GTP-gamma-S to inhibit forskolin-stimulation of adenylate cyclase. These results show an apparent functional imbalance between Gs and Gi/Go-mediated transduction mechanisms, with an increased efficacy of Gs activity likely due to the loss of Gi/Go inhibitory functions. Concomitantly with such transductional alteration detected in chronic diabetes, we observed a marked increase of the striatal content of met-enkephalin, which is known to utilize Gi/Go proteins for inhibition of adenylate cyclase. The measurement of other transmitters (vaso-active intestinal peptide, substance P, serotonin, noradrenaline, and dopamine) did not reveal any difference with respect to controls. The observed transductional defect in diabetic animals and the increased content and/or hyperinnervation by the metenkephalinergic system could be correlated as mutual compensatory mechanisms.
Abbracchio
M P
MP
Institute of Pharmacological Sciences, Faculty of Pharmacy, School of Medicine, University of Milan, Italy.
Di Luca
M
M
Di Giulio
A M
AM
Cattabeni
F
F
Tenconi
B
B
Gorio
A
A
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001927:Brain Diseases / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D003342:Corpus Striatum / Q000378:metabolism* / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000378:metabolism* / Q000503:physiopathology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D051381:Rats; D011954:Receptors, Dopamine / Q000502:physiology*
D011954:Receptors, Dopamine; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases