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Diabetes abolishes the GTP-dependent, but not the receptor-dependent inhibitory function of the inhibitory guanine-nucleotide-binding regulatory protein (Gi) on adipocyte adenylate cyclase activity.

ABSTRACT: Adipocyte membranes from control rats exhibited a functional Gi (inhibitory guanine-nucleotide-binding protein) activity which could be assessed either by the inhibitory action of low concentrations of guanosine 5-[beta gamma-imido]triphosphate (p[NH]ppG) upon forskolin-stimulated adenylate cyclase activity or by the inhibitory action of high concentrations of GTP upon isoprenaline-stimulated adenylate cyclase activity. When membranes from animals made diabetic with streptozotocin were used, then both such inhibitory functions of Gi were abolished. In contrast, receptor-mediated inhibitory responses of Gi, effected by N6-phenylisopropyl (adenosine), prostaglandin E2 or nicotinate, were either unchanged or even apparently more effective in membranes from diabetic animals. Induction of diabetes did not cause any change in the adipocyte plasma membrane levels of the alpha, GTP-binding subunits of either Gi1 or Gi2 or of Gs (stimulatory guanine-nucleotide-binding protein), but elicited an increase in the level of alpha-Gi3. The induction of diabetes reduced the specific activity of adenylate cyclase in adipocyte membranes and enhanced the stimulatory effect of isoprenaline. It is suggested that diabetes causes selective changes in the functioning of Gi in adipocyte membranes which removes the tonic GTP-dependent inhibitory function of this G-protein.

SUBMITTER: Strassheim D

PROVIDER: S-EPMC1131163 | biostudies-other | 1990 Mar

REPOSITORIES: biostudies-other

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Project description:We have previously shown that the stimulatory effects of guanine nucleotides, N-ethylcarboxamide-adenosine and other agonists on adenylate cyclase activity were diminished in aorta and heart sarcolemma of spontaneously hypertensive rats (SHR) [Anand-Srivastava (1988) Biochem. Pharmacol. 37, 3017-3022]. In the present studies, we have examined whether the decreased response of these agonists is due to the defective GTP-binding proteins (G-proteins) which couple the receptors to adenylate cyclase, and have therefore measured the levels of G-proteins in aorta and heart from SHR and their respective Wistar-Kyoto (WKY) controls by using pertussis toxin (PT)- and cholera toxin (CT)-catalysed ADP-ribosylations and immunoblotting techniques using specific antibodies against G-proteins. The labelling with [32P]NAD+ and PT identified a 40/41 kDa protein in heart and aorta from WKY and SHR and was significantly increased in the hearts (approximately 100%) and aorta (approximately 30-40%), from SHR as compared with WKY. Immunoblotting revealed an increase in the levels of the G-protein alpha-subunits Gi alpha-2 and Gi alpha-3 in heart and Gi alpha-2 in aorta, whereas no change in Go alpha was observed in heart from SHR and WKY. On the other hand, no differences were observed in CT labelling or immunoblotting of stimulatory G-protein (Gs) in heart and aorta from WKY and SHR. In addition, CT stimulated the adenylate cyclase activity in heart sarcolemma from WKY and SHR to a similar extent. These results were correlated with adenylate cyclase inhibition and stimulation by various hormones. Angiotensin II (AII), atrial natriuretic factor (ANF) and oxotremorine-mediated inhibition was found to be greater in SHR as compared with WKY, whereas the stimulatory effects of adrenaline, isoprenaline, dopamine and forskolin were diminished in SHR aorta as compared to WKY. These results indicate that regulatory protein G(i) is more expressed in SHR, which may be associated with the decreased responsiveness of stimulatory hormones and increased sensitivity of inhibitory hormones to stimulate/inhibit adenylate cyclase activity. It may thus be suggested that the enhanced G(i) activity may be one of the mechanisms responsible for the diminished vascular tone and impaired myocardial functions in hypertension.

Dataset Information

Diabetes abolishes the GTP-dependent, but not the receptor-dependent inhibitory function of the inhibitory guanine-nucleotide-binding regulatory protein (Gi) on adipocyte adenylate cyclase activity.

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