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 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.

Nitric oxide‐sensitive protein ADP‐ribosylation is altered in rat diabetic neuropathy

“…The results of our studies have demonstrated that G protein-dependent transduction mechanisms are altered in diabetic animals; these functional defects develop earlier in the retina than in other central nervous system CNS areas (Abbracchio et al, 1989(Abbracchio et al, , 1991Finco et al, 1992). We have shown that in the striatum of 14-week alloxan-diabetic rats, there is a reduced efficacy of Gi/Go proteins in the modulation of dopamine-sensitive adenylate cyclase; at earlier stages of diabetes no changes were observed (Abbracchio et al, 1989). G proteins in the retina are, however, more susceptible to diabetes.…”

Insulin Replacement Restores the Behavioral Effects of Quinpirole and Raclopride in Streptozotocin-Treated Rats

“…An important finding of this study is that STZ decreased quinpirole-and quinelorane-induced yawning as well as raclopride-induced catalepsy. Reduced sensitivity of STZ-treated rats to the behavioral effects of drugs acting on D2/D3 receptors parallels changes that can occur in DA receptors (e.g., receptor density and signaling) in hypoinsulinemic rats (Lozovsky et al, 1981, Rowland et al, 1985Abbracchio et al, 1989). To the extent that activity at different DA receptors accounts for the ascending (D3) and descending (D2) portions of the dose-response curve for yawning (Collins et al, 2005), the near absence of yawning observed in STZ-treated rats could indicate a decreased sensitivity of D3 receptors to quinpirole and quinelorane, an increased sensitivity of D2 receptors to quinpirole and quinelorane, or to changes in sensitivity at both receptor types.…”

“…The proximity of insulin and DA systems seems to have functional consequences. For example, rats with decreased circulating insulin showed decreased coupling of DA D2 receptors to G i/o proteins (Abbracchio et al, 1989) and reduced DAT activity (Owens et al, 2005) in the striatum. Food-deprived (i.e., hypoinsulinemic) rats also showed reduced DAT mRNA in the ventral tegmental area/substantia nigra and decreased DAT activity in the striatum (Patterson et al, 1998).…”

“…Food-deprived (i.e., hypoinsulinemic) rats also showed reduced DAT mRNA in the ventral tegmental area/substantia nigra and decreased DAT activity in the striatum (Patterson et al, 1998). Moreover, drug [alloxan or streptozotocin (STZ)]-induced hypoinsulinemia can alter [increase (Lozovsky et al, 1981;Trulson and Himmel, 1983;Serri et al, 1985) or decrease (Rowland et al, 1985)] the density of striatal D2 receptors and impair D2 receptorcoupled signal transduction (Abbracchio et al, 1989). Finally, hypoinsulinemic rats showed decreased synthesis (Kono and Takada, 1994), uptake (Owens et al, 2005), and turnover (Kwok and Juorio, 1986;Lim et al, 1994) of DA in the striatum.…”

Alterations of Hormone-Sensitive Adenylyl Cyclase System in the Tissues of Rats with Long-Term Streptozotocin Diabetes and the Influence of Intranasal Insulin

“…e AC effect of dopamine, contrary to the other investigated hormones, did not change in the diabetic brain. Earlier it was shown that dopamine-stimulated cAMP production in the brain of rats with 14-week alloxan DM or neonatal T2DM was markedly increased [16,33]. is may be due to a compensatory increase in the expression of G s protein-coupled D 1 -DAR, as in the case of short-term STZ T1DM [34].…”