Diabetes-induced alterations of central nervous system G proteins

Abstract

Previous studies from our laboratory have suggested that diabetes-associated central nervous system abnormalities are characterized by progressive alterations of neurotransmitters and of transductional Gi/Go proteins. In this study, we have further characterized these abnormalities in the striatum of alloxan-diabetic rats by means of adenosine 5'-diphosphate (ADP)-ribosylation, and Western and Northern blotting techniques. Fourteen weeks after diabetes induction, pertussis-toxin (PTX) catalyzed ADP-ribosylation of Gi/Go proteins was markedly reduced in diabetic animals, as shown by a clear decrease of 32P-ADPribose incorporation into G protein alpha subunits. In agreement with our previous pharmacological studies that showed a reduction of Gi-mediated modulation of adenylate cyclase activity only at this stage of diabetes, no changes in PTX-mediated ADP-ribosylation were observed earlier (5-wk diabetes). Immunoblotting studies performed by using antibodies selectively raised against Gi-2, Go, and Gs proteins did not reveal any differences between control and diabetic animals at any stage of diabetes. Similarly, the mRNAs corresponding to the alpha subunits of Gi-2, Go, and Gs proteins did not show any marked changes in chronic diabetic rats with respect to control animals. It is therefore concluded that diabetes is associated with development of a time-related alteration of cerebral Gi/Go proteins and that this defect is not owing to gross changes in either content of G proteins or mRNA level, but probably reflects modifications of G protein's structure or physiological status affecting the coupling with membrane effector systems and the sensitivity to PTX.

Striatal dopaminergic D1 and D2 receptors after intracerebroventricular application of alloxan and streptozocin in rat

“…Namely, agonist-induced reduction in cellular G protein levels can provide one mechanism for the development of receptor downregulation (Milligan, 1993). Recently, an apparent functional imbalance between Gs and Gi/G o protein mediated transduction mechanisms with an increased efficacy of Gs activity, probably due to the loss of G~/Go inhibitory functions, was found in the striatum and other tissues of diabetic animals (Abbracchio et al, 1989;Finco et al, 1992;Gawler et al, 1987;Hadjiconstantinou et al, 1988). The expression of G protein dysfunction in various tissues was present in diabetes of different duration, and in the striatum, not earlier than 5 weeks (Abbracchio et al, 1989).…”

“…Concerning the dopaminergic receptors, an increased D2 and decreased D 1 receptor density has been observed in this region (Lozovsky et al, 1981;Salkovid and Lackovid, 1992;Trulson and Himmel, 1983). Dopaminergic D1 and D2 receptors operate through signalling mechanism of stimulatory Gs and inhibitory Gi/Go proteins, respectively (Sibley and Monsma, 1990), whose altered function and content was found in various tissues of diabetic animals and man (Abbracchio et al, 1989;Finco et al, 1992;Gawler et al, 1987;Hadjiconstantinou et al, 1988;Livingstone et al, 1991;Palmer and Houslay, 1991).…”

Purinergic signalling and diabetes

“…Regarding the effect on the brain, in alloxan-diabetic rats, there are abnormalities in activity but not expression of G proteins in the striatum [146]. Diabetic encephalopathy results in cognitive impairment and modification of hippocampal function.…”

Guanosine‐5′‐(3‐O‐thio)triphosphate‐mediated stimulation of phosphoinositidase C in solubilized rat peripheral nerve myelin and its alteration in streptozotocin induced diabetes

“…The results indicate that under the reaction conditions used, maximal stimulation of enzyme activity in solubilized my elin from diabetic rats requires an appreciably higher concentration of GTPyS than is needed for this response in membranes from normal animals. Altered reactivity or impaired coupling of G proteins has been reported in preparations from a variety of tissues from alloxan or streptozotocin diabetic rats, including liver membranes, retinal homogenates, adipocytes, platelets, and synaptic membranes (Strassheim et al, 1990;Green and Johnson, 1991;Kowluru et al, 1992;Abbracchio et al, 1989;Finco et a]., 1992). A reduction of guanine nucleotide PIP,-specific PIC activity has also been found in platelets from diabetic patients (Bastyr and Vinik, 1992).…”