Denervation and hyperinnervation in the nervous system of diabetic animals: III. Functional alterations of G proteins in diabetic encephalopathy

Abstract 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 D 1 ‐receptor‐induced stimulation and D 2 ‐receptormediated 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 G i /G o proteins was also confirmed by the reduced ability of the GTP non‐hydrolyzable analog GTP‐γ‐S to inhibit forskolin‐stimulation of adenylate cyclase. These results show an apparent functional imbalance between G s and G i /G o ‐mediated transduction mechanisms, with an increased efficacy of G s activity likely due to the loss of G i /G o 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 G i /G o 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.