Functional coupling of the human dopamine D2 receptor with Gαi1, Gαi2, Gαi3 and Gαo G proteins: evidence for agonist regulation of G protein selectivity

Gazi, Lucien; Nickolls, Sarah A.; Strange, Philip G.

doi:10.1038/sj.bjp.0705116

Cited by 84 publications

(87 citation statements)

References 42 publications

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“…For one, it has been shown that dopamine D 2 receptors modulate the level of cAMP in mice striatum via isoform 5 of AC. However, D 2 receptors preferentially couple to the G o subtype of G-proteins (29), which, as shown previously, have practically no influence on AC5 activity in vitro (30). Thus, it is possible that the effect of D 2 receptors on cAMP accumulation is relatively small compared to the basal level of AC activation and therefore remains hidden in a given system.…”

Section: Discussionsupporting

confidence: 61%

Modulation of Adenylyl Cyclase Activity in Rat Striatal Homogenate by Dopaminergic Receptors

2008

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Abstract. We have characterized the modulation of adenylyl cyclase (AC) activity by ligands of dopaminergic receptors in rat striatal homogenate and compared the results with receptorligand binding affinities. Despite the fact that rat striatum contains high level of both dopamine D 1 and D 2 receptors, only the D 1 -specific AC activation by agonists could be determined. All D 1 -receptor agonists (dopamine, dihydrexidine, and A 77636) used were able to increase cAMP accumulation in a concentration-dependent manner, while D 1 -receptor antagonists (SCH23390, SKF83566, and butaclamol) blocked the effects induced by the aforementioned agonists. At the same time, the D 2 -receptor agonist quinpirole and antagonist sulpiride had no effect on cAMP accumulation in striatal homogenate neither on the basal level nor on the activated level of AC, while inhibited [

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Section: Discussionsupporting

confidence: 61%

Modulation of Adenylyl Cyclase Activity in Rat Striatal Homogenate by Dopaminergic Receptors

2008

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“…In the simplest view, these compounds would induce similar increases in activity of mGluR5 regardless of the signaling pathway or cell population involved. However, a growing body of evidence suggests that different traditional orthosteric agonists can differentially activate different signaling pathways of a single GPCR, a phenomenon referred to as agonist receptor trafficking (Berg et al, 1998;Brink et al, 2000;Gazi et al, 2003). Based on this, it is possible that allosteric potentiators of mGluRs could differentially regulate coupling of these receptors to different signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) Acts through a Novel Site as a Positive Allosteric Modulator of Group 1 Metabotropic Glutamate Receptors

Chen¹,

Goudet²,

Pin³

et al. 2007

Mol Pharmacol

108

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Recent studies suggest that a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor (mGluRs), mGluR5, termed 4-nitro-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (VU-29), potentiates mGluR5 responses by actions at a site that is overlapping with the binding site of 2-methyl-6-(phenylethynyl)pyridine (MPEP), a previously identified negative allosteric modulator of this receptor. It is interesting that a structurally distinct PAM, N-{4-Chloro-2- [(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA), does not to bind to the MPEP site. We now report that CPPHA potentiates mGluR5 responses by a mechanism that is distinct from that of VU-29. VU-29-and CPPHA-induced potentiation of mGluR5 responses are blocked by a neutral ligand at the MPEP allosteric site termed 5-methyl-2-(phenylethynyl)pyridine (5MPEP). However, increasing concentrations of 5MPEP induce parallel rightward shifts in the VU-29 concentration-response curve, whereas 5MPEP inhibits CPPHA potentiation in a noncompetitive manner. Consistent with this, a mutation (A809V/mGluR5) that reduces binding of ligands to the MPEP site eliminates the effect of VU-29 but has no effect on the response to CPPHA. On the other hand, a mutation (F585I/mGluRs) that eliminates the effect of CPPHA does not alter the response to VU-29. CPPHA is also a PAM at mGluR1. It is interesting that the corresponding mutation of F585I/mGluR5 in mGluR1 (F599I/ mGluR1) eliminates CPPHA's effect without altering the potentiation of a known PAM of mGluR1, (S)-2-(4-fluorophenyl)-1-(toluene-4-sulfonyl)pyrrolidine (Ro 67-7476). Likewise, another mutation (V757L/mGluR1) that abolishes potentiation of Ro 67-7476 has no effect on CPPHA. Finally, CPPHA does not displace binding of a radioligand for the mGluR1 allosteric antagonist characterized previously. Together, these data suggest that CPPHA acts at a novel allosteric site on both mGluR1 and -5 to potentiate responses to activation of these receptors.Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. In addition to eliciting fast excitatory synaptic responses, glutamate has neuromodulatory effects by activation of G protein-coupled receptors (GPCRs) termed metabotropic glutamate receptors (mGluRs). There are eight subtypes of mGluRs divided into three groups. Group I mGluRs (mGluR1 and mGluR5) couple to G␣ q/11 and activate phospholipase C. Group II (mGluR2 and mGluR3) and group III (mGluR4, mGluR6, mGluR7, and mGluR8) mGluRs couple to the inhibition of adenylyl cyclase and other effectors through G␣ i/o (Conn and Pin,

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“…Membranes of wild-type Sf9 cells or of Sf9 cells infected with DmDopEcR-GFP were prepared as described previously (Gazi et al, 2003 Competition experiments were done in duplicate, with increasing concentrations of ligand from 1 fmol to 1 mM and a radioligand concentra-tion equivalent to its K D (10 nM). When (Ϫ)-AD, DA, and (Ϫ)-NA were used, incubations were performed in the dark, and 0.1 M ascorbic acid was added to the binding buffer to prevent oxidation.…”

Section: Methodsmentioning

confidence: 99%

Rapid, Nongenomic Responses to Ecdysteroids and Catecholamines Mediated by a NovelDrosophilaG-Protein-Coupled Receptor

Srivastava¹,

Yu²,

Kennedy³

et al. 2005

J. Neurosci.

215

214

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Nongenomic response pathways mediate many of the rapid actions of steroid hormones, but the mechanisms underlying such responses remain controversial. In some cases, cell-surface expression of classical nuclear steroid receptors has been suggested to mediate these effects, but, in a few instances, specific G-protein-coupled receptors (GPCRs) have been reported to be responsible. Here, we describe the activation of a novel, neuronally expressed Drosophila GPCR by the insect ecdysteroids ecdysone (E) and 20-hydroxyecdysone (20E). This is the first report of an identified insect GPCR interacting with steroids. The Drosophila melanogaster dopamine/ecdysteroid receptor (DmDopEcR) shows sequence homology with vertebrate ␤-adrenergic receptors and is activated by dopamine (DA) to increase cAMP levels and to activate the phosphoinositide 3-kinase pathway. Conversely, E and 20E show high affinity for the receptor in binding studies and can inhibit the effects of DA, as well as coupling the receptor to a rapid activation of the mitogen-activated protein kinase pathway. The receptor may thus represent the Drosophila homolog of the vertebrate "␥-adrenergic receptors," which are responsible for the modulation of various activities in brain, blood vessels, and pancreas. Thus, DmDopEcR can function as a cell-surface GPCR that may be responsible for some of the rapid, nongenomic actions of ecdysteroids, during both development and signaling in the mature adult nervous system.

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Functional coupling of the human dopamine D₂ receptor with Gα_i1, Gα_i2, Gα_i3 and Gα_o G proteins: evidence for agonist regulation of G protein selectivity

Cited by 84 publications

References 42 publications

Modulation of Adenylyl Cyclase Activity in Rat Striatal Homogenate by Dopaminergic Receptors

Modulation of Adenylyl Cyclase Activity in Rat Striatal Homogenate by Dopaminergic Receptors

N-{4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide (CPPHA) Acts through a Novel Site as a Positive Allosteric Modulator of Group 1 Metabotropic Glutamate Receptors

Rapid, Nongenomic Responses to Ecdysteroids and Catecholamines Mediated by a NovelDrosophilaG-Protein-Coupled Receptor

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