Receptors couple to L‐type calcium channels via distinct G<sub>o</sub> proteins in rat neuroendocrine cell lines

Degtiar, Vadim E.; Harhammer, Rainer; Nürnberg, Bernd

doi:10.1111/j.1469-7793.1997.321bk.x

Cited by 44 publications

(34 citation statements)

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“…Activation of the K ATP channel, which hyperpolarizes the cell membrane, prevents insulin secretion from pancreatic islets, and modulation of the channel activity has been a therapeutic for treating type II diabetes. G o2 can also mediate somatostatin-induced inhibition of Ca 2+ currents in the GH3 rat neuroendocrine cell line (46). Intracellular calcium is a central regulator for triggering the secretory machinery.…”

Section: Resultsmentioning

confidence: 99%

Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins

Wang

Park

Bajpayee

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Insulin secretion by pancreatic β cells is a complex and highly regulated process. Disruption of this process can lead to diabetes mellitus. One of the various pathways involved in the regulation of insulin secretion is the activation of heterotrimeric G proteins. Bordetella pertussis toxin (PTX) promotes insulin secretion, suggesting the involvement of one or more of three G i and/or two G o proteins as suppressors of insulin secretion from β cells. However, neither the mechanism of this inhibitory modulation of insulin secretion nor the identity of the G i/o proteins involved has been elucidated. Here we show that one of the two splice variants of G o , G o2 , is a key player in the control of glucose-induced insulin secretion by β cells. Mice lacking G o2 α, but not those lacking α subunits of either G o1 or any G i proteins, handle glucose loads more efficiently than wild-type (WT) mice, and do so by increased glucose-induced insulin secretion. We thus provide unique genetic evidence that the G o2 protein is a transducer in an inhibitory pathway that prevents damaging oversecretion of insulin.D iabetes mellitus is characterized by abnormalities in insulin secretion that may be either a primary defect, as seen in type I diabetes, or a secondary defect, where secretion is inadequate to overcome primary insulin resistance seen in type II diabetes. In either case, individuals are hyperglycemic. Insulin is the master controller of glucose metabolism, and its release from β cells is tightly regulated. Many factors, including hormones, neuropeptides, and neurotransmitters regulate insulin secretion by activating heterotrimeric G proteins, which can control the output of insulin in response to physiological demands (1, 2). Activation of pathways mediated by G s and/or G q/11 stimulates insulin release from β cells (3, 4). The involvement of G i /G o proteins as inhibitors of insulin secretion from β cells was originally uncovered in studies on the Bordetella pertussis toxin (PTX) in animals and cells (5, 6). Previously called islet-activating protein (IAP), PTX was shown to lower glucose levels in the bloodstream by increasing insulin secretion from β cells (7). The enhanced secretion resulted from the removal of tonic inhibition exerted by neurotransmitters/hormones, including adrenaline (8), galanin (9), and ghrelin (10). PTX catalyzes the ADP ribosylation of a carboxyl-terminal cysteine present in the α subunits of the G protein subgroup now referred to as G i /G o (11). This event causes these G proteins to become uncoupled from receptors and thereby disrupts the signal transduction process. The nonsensory PTX-sensitive G i /G o G proteins encompass three G i 's (G i1 , G i2 , and G i3 ), and two G o 's (G o1 and G o2 ). The α subunits of G i and G o display extensive homology and are functionally similar as they can be activated by the same or similar receptors and appear to signal to partially overlapping sets of effectors (12). This has raised questions whether the individual G i and G o proteins function dis...

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Section: Resultsmentioning

confidence: 99%

Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins

Wang

Park

Bajpayee

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Purified ␤␥-subunits and ␣ i /␣ o -subunits from brain were kindly donated by Dr. G. Schultz (Institut fü r Pharmakologie, Freie Universität, Berlin, Germany) (9). The GST fusion protein containing a carboxylterminal fragment (residues 546 -670) of ␤-adrenergic receptor kinase-1 (␤ARK1-CT/GST) and the corresponding GST protein were a gift of Dr. R. J. Lefkowitz (Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC) (10).…”

Section: Methodsmentioning

confidence: 99%

Inhibitory Effect of Isoproterenol on NADPH-dependent H2O2 Generation in Human Adipocyte Plasma Membranes Is Mediated by βγ-Subunits Derived from Gs

Krieger-Brauer¹,

Medda²,

Sattel³

et al. 2000

Journal of Biological Chemistry

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Previous studies revealed that human fat cell plasma membranes contain a multireceptor-linked H 2 O 2 -generating system that is under antagonistic control by hormones and cytokines and is stimulated by insulin via G␣ i2 . In this report, it is shown that the inhibitory action of the ␤-adrenergic agonist isoproterenol is mediated by G protein ␤␥-subunits, based on observations that its action was specifically reversed by anti-G␤ antibodies or a C-terminal ␤-adrenergic receptor kinase-1 fragment containing the G␤␥-binding site of the enzyme, and was mimicked by exogenously supplied G protein ␤␥-sub- There is growing evidence that redox-active biomolecules play important roles in signaling by hormones and cytokines (1-3). Ligand-induced changes in cellular redox status modulate tyrosine phosphorylation-dependent pathways of signal transduction; alter DNA binding and transactivation activities of many transcriptional activators; and may influence key steps in the synthesis, degradation, and action of cAMP and cGMP as well (2, 3). Previous work showed that human fat cells possess a plasma membrane-bound H 2 O 2 -generating system that is under antagonistic control by a large and diverse group of hormones and cytokines, including insulin, the ␤-adrenergic agonist isoproterenol, and different isoforms of fibroblast and platelet-derived growth factors (4 -7). The mechanisms by which hormones and cytokines regulated NADPH-dependent H 2 O 2 generation were confined to the plasma membrane, operated in the absence of ATP, and were independent of soluble second messengers, indicating that established pathways of signal transduction were not involved. These findings placed human fat cell oxidase in a position comparable with adenylyl cyclase and suggested a physical interaction between receptors and NADPH oxidase or receptor-effector coupling via signaltransducing protein(s). Indeed, recent work revealed that the stimulatory effect of insulin on NADPH-dependent H 2 O 2 generation is transduced via G␣ i2 (7).In this study, we have investigated whether the effects of the ␤-adrenergic agonist isoproterenol are also mediated by heterotrimeric G protein(s). Using specific antibodies against the ␣-and ␤-subunits of heterotrimeric G proteins and a peptide that specifically binds G␤␥, it is shown that the inhibitory effects of isoproterenol on NADPH-dependent H 2 O 2 generation are mediated by ␤␥-subunits. Taking advantage of the unique properties of a commercially available antibody directed against residues 100 -119 within the ␣-helical domain of G␣ s (K-20) and of the peptide corresponding to its target sequence, which are summarized in a recent publication (8), it is shown that the ␤␥-subunits mediating the inhibitory action of isoproterenol were derived from G s .

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“…The activation is terminated by a GTPase activity intrinsic to the α-subunit. It is also widely accepted that G o α is primarily responsible for the modulation of neuronal voltage-dependent Ca 2+ channels [4,7,8,28], although several Gβγ subunits are able to transduce the signal to Ca 2+ channels [14,17]. We found that hypoxia induced an average decrease of about 25% in the levels of G i/o immunoreactivity.…”

Section: Discussionmentioning

confidence: 52%

“…Indeed, it is already established that membrane-delimited G protein regulation of Ca 2+ channels is common in neurons and that the G protein involved in this inhibition is PTX sensitive [7,12,16,36]. Growing evidence strongly implicates G o rather than G i in this regulation, which could also affect the suppression of neurotransmitter release that is mediated by receptors on presynaptic neurons [4,7,8,28]. Furthermore, membrane-delimited G protein regulation of I Ca by DA has been shown in chick sensory and sympathetic neurons [27].…”

Section: Discussionmentioning

confidence: 99%

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Role of the D 2 dopamine receptor in molecular adaptation to chronic hypoxia in PC12 cells

Kobayashi¹,

Conforti²,

Zhu³

et al. 1999

Pfl�gers Archiv European Journal of Physiology

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We have previously shown that pheochromocytoma (PC12) cells rapidly depolarize and undergo Ca 2+ influx through voltage-dependent Ca 2+ channels in response to moderate hypoxia and that intracellular free Ca 2+ is modulated by activation of dopamine D 2 receptors in this cell type. The present study shows that D 2 (quinpirole-mediated) inhibition of a voltage-dependent Ca 2+ current (I Ca ) in PC12 cells is dramatically attenuated after chronic exposure to moderate hypoxia (24 h at 10% O 2 ). Pretreatment of cells with pertussis toxin abolished D 2 -mediated inhibition of I Ca . The D 2 -induced inhibition of I Ca did not depend on protein kinase A (PKA), as it persisted both in the presence of a specific PKA inhibitor (PKI) and in PKA-deficient PC12 cells. Prolonged exposure to hypoxia (24 h) significantly reduced the level of G i/o α immunoreactivity, but did not alter Gβ levels. Furthermore, dialysis of recombinant G o α protein through the patch pipette restored the inhibitory effect of quinpirole in cells chronically exposed to hypoxia. We conclude that the attenuation of the D 2 -mediated inhibition of I Ca by chronic hypoxia is caused by impaired receptor-G protein coupling, due to reduced levels of G o α protein. This attenuated feedback modulation of I Ca by dopamine may allow for a more sustained Ca 2+ influx and enhanced cellular excitation during prolonged hypoxia.

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Receptors couple to L‐type calcium channels via distinct G_o proteins in rat neuroendocrine cell lines

Cited by 44 publications

References 59 publications

Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins

Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins

Inhibitory Effect of Isoproterenol on NADPH-dependent H2O2 Generation in Human Adipocyte Plasma Membranes Is Mediated by βγ-Subunits Derived from Gs

Role of the D 2 dopamine receptor in molecular adaptation to chronic hypoxia in PC12 cells

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Receptors couple to L‐type calcium channels via distinct Go proteins in rat neuroendocrine cell lines

Cited by 44 publications

References 59 publications

Augmented glucose-induced insulin release in mice lacking G o2 , but not G o1 or G i proteins

Augmented glucose-induced insulin release in mice lacking G o2 , but not G o1 or G i proteins

Inhibitory Effect of Isoproterenol on NADPH-dependent H2O2 Generation in Human Adipocyte Plasma Membranes Is Mediated by βγ-Subunits Derived from Gs

Role of the D 2 dopamine receptor in molecular adaptation to chronic hypoxia in PC12 cells

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Resources

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Receptors couple to L‐type calcium channels via distinct G_o proteins in rat neuroendocrine cell lines

Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins

Augmented glucose-induced insulin release in mice lacking G _o2 , but not G _o1 or G _i proteins