Altered G-protein expression and adenylate cyclase activity in platelets of non-insulin-dependent diabetic (NIDDM) male subjects

Livingstone, Callum; McLellan, A. R.; McGregor, M.; Wilson, Andrew; Connell, John; Small, M.; Milligan, Graeme; Paterson, Ken; Houslay, Miles D.

doi:10.1016/0925-4439(91)90050-j

Cited by 44 publications

(31 citation statements)

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“…This is in good agreement with many reports about abnormalities in expression and functional activity of heterotrimeric G proteins, G i proteins in particular, in the case of DM and a high level of plasma glucose [9,[25][26][27][28][29][30][31][32]. A decrease of expression of G i protein a subunits is revealed in the tissues of diabetic patients and animals with different models of DM and insulin resistance-associated obesity.…”

Section: Discussionsupporting

confidence: 78%

“…The level of all subtypes of Ga i subunits is modestly decreased in the blood vessels from rats with streptozotocin-induced DM [30]. In the platelets from patients with type 2 DM the levels of Ga i2 and Ga i3 subunits are 49 and 75%, respectively, of those in platelets from control subjects, while Ga i1 is not expressed at all [27]. A similar picture has been observed in the hepatocytes from streptozotocin-treated rats [33].…”

Section: Discussionsupporting

confidence: 57%

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Intranasal insulin affects adenyl cyclase system in rat tissues in neonatal diabetes

Chistyakova

Derkach

et al. 2011

Open Life Sciences

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Intranasal insulin affects adenyl cyclase system in rat tissues in neonatal diabetes Abbreviations:AC -adenylyl cyclase; AC system -adenylyl cyclase signaling system; DM -diabetes mellitus; EMD-386088 -5 -c h l o r o -2 -m e t h y l -3 -( 1 , 2 , 3 , 6 -tetrahydro-4-pyridinyl)-1H-indole; GppNHp -b,g-imidoguanosine-5'-triphosphate; 5-HT receptor -5-hydroxytryptamine receptor; hCG -human chorionic gonadotropin; PACAP-38 -pituitary adenylyl cyclase-activating peptide-38. IntroductionHypertension, coronary heart diseases, atherosclerosis, nephropathy, retinopathy, neuropathy, cognitive deficit and disorders of the reproductive system are the most common complications of diabetes mellitus (DM) [1][2][3]. Chronic hyperglycemia is quite often an important contributing factor in the development of these complications. Many hormone-and growth factorregulated signaling pathways, such as the adenylyl cyclase (AC) signaling system, phospholipase C/protein kinase C signaling system and the cascade of mitogenactivated protein kinases are implicated in the regulation of the cardiovascular, nervous and reproductive systems and aberration of their functional activity in DM may contribute to complications of this disease [4][5][6][7][8]. It has been shown that in experimental types 1 and 2 DM the functional activity of hormone-sensitive AC system in the skeletal muscles, myocardium, testis, ovaries, uterus and brain of diabetic rats and the sensitivity of this system to hormones regulating AC activity are changed in tissue-and hormone-specific manner [6][7][8][9][10][11][12].The most significant changes of hormonal sensitivity of AC system were found in the myocardium, testis and Abstract:The changes in hormone-regulated adenylyl cyclase (AC) signaling system implicated in control of the nervous, cardiovascular and reproductive systems may contribute to complications of diabetes mellitus (DM). We investigated the functional state of AC system in the brain, myocardium, ovary and uterus of rats with neonatal DM and examined the influence of intranasally administered insulin on the sensitivity of this system to biogenic amines and polypeptide hormones. The regulatory effects of somatostatin and 5-HT 1B R-agonist 5-nonyloxytryptamine acting via G i protein-coupled receptors were significantly decreased in DM and partially restored in insulin-treated rats. The effects of hormones, activators of AC, are changed in tissue-and receptorspecific manner, and intranasal insulin restored the effects rather close to the level in control. In insulin-treated non-diabetic rats, AC stimulating effects of isoproterenol and relaxin in the myocardium and of human chorionic gonadotropin in the ovaries were decreased, while the effects of hormones, inhibitors of AC, were increased. These data indicate that with intranasal insulin, G i protein-mediated signaling pathways continue to gain strength. The obtained data on the influence of hormones on AC system in the brain, myocardium, ovary and uterus allow looking anew into the mechanisms of therapeutic ...

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Section: Discussionsupporting

confidence: 78%

Section: Discussionsupporting

confidence: 57%

Intranasal insulin affects adenyl cyclase system in rat tissues in neonatal diabetes

Chistyakova

Derkach

et al. 2011

Open Life Sciences

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“…In hepatocytes of streptozotocin-induced diabetic rats [25,26] there is a loss of Gi function which appears to result from both a reduction in the expression of Gi-2 and also its increased phosphorylation by protein kinase C. Treatment of a variety of different cell types with tumour promoting phorbol esters has been shown to lead to the loss of guanine nucleotide-elicited, G~-mediated inhibition of adenylate cyclase activity [13,37]. Similar observations of crippled G~ function have also been seen in cells challenged with ligands which stimulate phospholipid metabolism or with DAG [13], suggesting that it is the activation of protein kinase C which provides the molecular basis of this phenomenon.…”

Section: Resultsmentioning

confidence: 99%

“…Western blotting was performed essentially as described before by us (see e.g. [37]) using a 2 h transfer time onto nitrocellulose paper in blotting buffer (0.005% SDS, 5 g/l Tris base and 14.4 g/l glycine). The blots were blocked with 4% (w/v) skimmed milk, 2% (v/v) donkey serum in PBS, 0.05% NP-40 and 20%-methanol for 2 h, followed by an incubation with the designated isozyme specific antiserum (appropriately diluted in 0.02% thimerosal) overnight.…”

Section: Immunoblotting Of Protein Kinase C Isozymesmentioning

confidence: 99%

Diabetes induces selective alterations in the expression of protein kinase C isoforms in hepatocytes

et al. 1993

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Membrane and cytosol fractions from hepatocytes of both normal and streptozotocin-induced diabetic animals were probed with a panel of polyclonal anti-peptide antisera in order to identify protein kinase C (PKC) isoforms. Immunoreactive species were noted with antisera specific for ~ (-81 kDa), fl-ll (-82 kDA), E (--95 kDa) and ~" (~ 79 kDa). In addition, a species migrating with an apparent size of -94 kDa was also detected in cytosol fractions using an antiserum specific for PKC-c~. Each of these species was specifically displaced when the PKC-isoform specific peptide was included in the immunodetection system. No immunoreactive species consistent with the presence of the fl-I, 7, ~ and 1/isoforms of protein kinase C was observed. Induction of diabetes using streptozotocin invoked selective alterations in the expression of PKC isoforms which were reversed upon insulin therapy. In the cytosol fraction, marked increases of ~ 3-fold occurred in levels of the fl-I1 isoform and the ~ 90 kDa (upper) form of PKC-~, with no apparent/little change in the levels of the -81 kDa (lower) form of PKC-cc and those of PKC-~'. Diabetes induction also appeared to have elicited the translocation of PKC-fl-II and the -81 kDa (lower) form of PKC-c~ to the membrane fraction where immunoreactivity for these species was now apparent. The level of PKC-e, which was noted only in membrane fractions, was also increased upon induction of diabetes. It is suggested that the selective alterations in the expression of PKC isoforms occurring upon streptozotocin-induced diabetes may lead to altered cellular functioning and underly defects in inhibitory G-protein functioning and insulin action which characterise this animal model of diabetes.

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“…Electrophoresis was performed on an 8 % acrylamide gel (running buffer 25 mM Tris, 0n19 M glycine, 3n5 mM SDS) at 7 mA\gel overnight or 60 mA\gel for 3-4 h with cooling. Western blotting was performed essentially as described previously by us [30] using a 1 h transfer time on to nitrocellulose paper. The blots were blocked for 2 h in 5 % (w\v) skimmed milk in Tris-buffered saline (TBS), followed by an incubation with the designated antiserum overnight.…”

Section: Western-blot Analysismentioning

confidence: 99%

Co-transfection with protein kinase D confers phorbol-ester-mediated inhibition on glucagon-stimulated cAMP accumulation in COS cells transfected to overexpress glucagon receptors

Tobias

Connell

Houslay

1997

Biochemical Journal

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Glucagon elicited a profound increase in the intracellular cAMP concentration of COS-7 cells which had been transiently transfected with a cDNA encoding the rat glucagon receptor and under conditions where cAMP phosphodiesterase activity was fully inhibited. This was achieved in a dose-dependent fashion with an EC50 of 1.8±0.4 nM glucagon. In contrast with previous observations made using hepatocytes [Heyworth, Whetton, Kinsella and Houslay (1984) FEBS Lett. 170, 38–42], treatment of transfected COS-7 cells with PMA did not inhibit the ability of glucagon to increase intracellular cAMP levels. PMA-mediated inhibition was not conferred by treatment with okadaic acid, nor by co-transfecting cells with cDNAs encoding various protein kinase C isoforms (PKC-α, PKC-βII and PKC-ϵ) or with the PMA-activated G-protein-receptor kinases GRK2 and GRK3. In contrast, PMA induced the marked inhibition of glucagon-stimulated cAMP production in COS-7 cells that had been co-transfected with a cDNA encoding protein kinase D (PKD). Such inhibition was not due to an action on the catalytic unit of adenylate cyclase, as forskolin-stimulated cAMP production was unchanged by PMA treatment of COS cells that had been co-transfected with both the glucagon receptor and PKD. PKD transcripts were detected in RNA isolated from hepatocytes but not from COS-7 cells. Transcripts for GRK2 were present in hepatocytes but not in COS cells, whereas transcripts for GRK3 were not found in either cell type. It is suggested that PKD may play a role in the regulation of glucagon-stimulated adenylate cyclase.

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Altered G-protein expression and adenylate cyclase activity in platelets of non-insulin-dependent diabetic (NIDDM) male subjects

Cited by 44 publications

References 55 publications

Intranasal insulin affects adenyl cyclase system in rat tissues in neonatal diabetes

Intranasal insulin affects adenyl cyclase system in rat tissues in neonatal diabetes

Diabetes induces selective alterations in the expression of protein kinase C isoforms in hepatocytes

Co-transfection with protein kinase D confers phorbol-ester-mediated inhibition on glucagon-stimulated cAMP accumulation in COS cells transfected to overexpress glucagon receptors

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