Go, a guanine nucleotide-binding protein: immunohistochemical localization in rat brain resembles distribution of second messenger systems.

Worley, PF; Baraban, JM; Dop, Cornelis Van; Neer, Eva J.; Snyder, S. H.

doi:10.1073/pnas.83.12.4561

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

1986

DOI: 10.1073/pnas.83.12.4561

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Go, a guanine nucleotide-binding protein: immunohistochemical localization in rat brain resembles distribution of second messenger systems.

PF Worley¹,

JM Baraban²,

Cornelis Van Dop³

et al.

Abstract: We have localized a guanine nucleotide-bind-

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Cited by 149 publications

(99 citation statements)

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“…A recent paper by Hescheler et al 13 indicates that α o may play a pivotal role in regulating Ca 2+ channel function in neurons. Furthermore, the recently reported co-localization of α o immunoreactivity and phorbol ester binding in brain 14 suggests the possibility that physiological processes regulated by this G protein may be mediated by protein kinase C. …”

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confidence: 98%

G proteins as regulators of ion channel function

Dunlap

Holz

Rane

1987

Trends in Neurosciences

172

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Virtually unknown just a decade ago, GTP-binding proteins (G proteins) have become a major focus of current research. This family of closely related proteins transduce extracellular signals (such as hormones, neurotransmitters and sensory stimuli) into effector responses 1,2 . It is now evident that ion channel permeability is one such effector response. In fact, the striking increase in the frequency of reports that demonstrate G protein-regulated ion channel function suggests that channels whose permeability mechanism can be altered by a G protein-mediated process may be more the rule than the exception. It is well-known that the cAMP-dependent modulation of ion channels is under the control of G proteins that regulate adenylate cyclase activity 3,4 . However recent studies demonstrate that G proteins also transduce agonist-induced changes in channel activity that do not involve adenylate cyclase. It is on this aspect of G protein signal transduction that this review will focus.Much of our information on the mechanisms underlying G protein function comes from research on G s , the regulatory protein mediating hormonal stimulation of adenylate cyclase. According to one presently accepted model (for review see Ref. 5), G s , in the non-activated state, exists as a heterotrimer of α-, β-and γ-subunits with GDP bound on the α-subunit (G-GDP). The interaction of agonist, receptor, and G-GDP accelerates the exchange of GTP for bound GDP. Binding of GTP by the α-subunit stimulates both the dissociation of G-GTP from the agonist-receptor complex, and the dissociation of the G protein itself into α-GTP (the active subunit with GTPase activity) and βγ (the regulatory dimer). Via a mechanism that remains to be identified, α-GTP promotes an increase in adenylate cyclase activity. The action of α-GTP is terminated through the α-subunit-mediated hydrolysis of GTP followed by reassociation of the α-subunit with free βγ to reform the inactive G-GDP. The agonistinduced activation of a G protein and its deactivation through hydrolysis of GTP is illustrated schematically by the cycle in Fig. 1. This general scheme of events has been postulated to underlie the mechanism of action of other, more recently discovered G proteins (G i and G o ) 6-8 , although the receptors and, in some cases, the effector enzymes involved are different. In addition to its inhibitory role in the regulation of adenylate cyclase, a G i -like protein may, for example, control the activity of other second messenger-generating enzymes such as phospholipase C or phospholipase A 2 9-12 . Similarly, it has been thought that G o , a regulatory protein found in abundance in neural tissue (~1% of total protein), might also be linked to enzyme effectors other than adenylate cyclase but, until recently, the α-subunit of G o has had no demonstrable physiological function. A recent paper by Hescheler et al. 13 indicates that α o may play a pivotal role in regulating Ca 2+ channel function in neurons. Furthermore, the recently reported co-localization of α o i...

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mentioning

confidence: 98%

G proteins as regulators of ion channel function

Dunlap

Holz

Rane

1987

Trends in Neurosciences

172

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“…G o has a less ubiquitous expression pattern than G i or G s and is highly expressed in the central and peripheral nervous systems, where it was originally identified (16,17). G o is also expressed in the heart and in the endocrine system, including the pituitary gland and pancreatic islets (18,19).Insulin secretion can be modulated through cAMP-dependent and -independent pathways (1, 20). Activation of G s in pancreatic β cells enhances insulin release through an adenylyl cyclase/ cAMP-mediated mechanism.…”

mentioning

confidence: 99%

mentioning

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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“…These data suggest that the pertussis toxin substrate Gi, Go or a Gi/Go-like Gprotein may be involved in the phosphoinositide response in some cell types. Indirect evidence from Snyder's laboratory showed that immunohistochemical localizations of Go and protein kinase C correspond in many areas of the brain suggesting a potential role for Go in the regulation of the phosphoinositide response [21]. Reconstitution experiments using purified Go or Gi will provide valuable information to the above observations.…”

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confidence: 99%

Receptor‐phosphoinositidase C coupling Multiple G‐proteins?

Hughes

1987

FEBS Letters

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Recent evidence has suggested that receptor‐mediated phosphoinositide turnover, like that of the adenylate cyclase cAMP pathway, is regulated by guanine nucleotides. It is likely that one or more guanine nucleotide‐binding proteins (G‐proteins) couple calcium‐mobilizing receptors to the activation of phosphoinositidase C. Recent studies utilizing various bacterial toxins have strongly suggested the presence of multiple G‐proteins in the regulation of receptor‐phosphoinositidase C coupling in a variety of cell types.

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Go, a guanine nucleotide-binding protein: immunohistochemical localization in rat brain resembles distribution of second messenger systems.

Abstract: We have localized a guanine nucleotide-bind-

Cited by 149 publications

References 30 publications

G proteins as regulators of ion channel function

G proteins as regulators of ion channel function

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

Receptor‐phosphoinositidase C coupling Multiple G‐proteins?

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Go, a guanine nucleotide-binding protein: immunohistochemical localization in rat brain resembles distribution of second messenger systems.

Abstract: We have localized a guanine nucleotide-bind-

Cited by 149 publications

References 30 publications

G proteins as regulators of ion channel function

G proteins as regulators of ion channel function

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

Receptor‐phosphoinositidase C coupling Multiple G‐proteins?

Contact Info

Product

Resources

About

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