W276 Mutation in the Endothelin Receptor Subtype B Impairs Gq Coupling but Not Gi or Go Coupling

Imamura, Fumiaki; Arimoto, Ikuyo; Fujiyoshi, Yoshinori; Doi, Tomoko

doi:10.1021/bi991981z

Cited by 30 publications

(16 citation statements)

References 32 publications

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“…A single receptor could exist under multiple conformations that are specific for a particular G protein/effector pathway, as already suggested for other receptors such as endothelin receptor subtype B or α 1B ‐adrenergic receptor (Perez et al . 1996; Imamura et al . 2000).…”

Section: Discussionmentioning

confidence: 99%

Further evidence that the CCK₂ receptor is coupled to two transduction pathways using site‐directed mutagenesis

Pommier

Marie-Claire

Nascimento

et al. 2003

Journal of Neurochemistry

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A heterogeneity of CCK 2 receptors has been reported which could correspond to different states of coupling to G proteins and/or association with different second messenger systems. To investigate these hypotheses, the wild-type CCK 2 receptor and three mutants F347A, D100N and K333M/K334T/R335L, expected to modify the coupling of the G protein with the third intracellular loop of the receptor, were transfected into Cos-7 cells and their binding and signalling properties were evaluated using the natural ligand CCK 8 . Activation of wild-type as well as F347A, D100N or K333M/K334T/R335L CCK 2 receptors by this ligand led to a similar arachidonic acid release which was blocked by pertussis toxin and the phospholipase A 2 inhibitor, mepacrine. Nevertheless, in contrast to the wild-type CCK 2 receptor, addition of CCK 8 to cells transfected with the F347A or K333M/K334T/R335L mutants did not result in the production of inositol phosphates while the maximum increase in this second messenger formation was reduced by 30% with the D100N mutant. Taken together, these results suggest that the CCK 2 receptor is coupled to two G proteins and that Phe347 and the cluster of basic residues K333/K334/R335 probably play a key role in G q protein stimulation leading to inositol phosphate production but not in activation of the G protein coupled to phospholipase A 2 . These data bring additional support at the molecular level to the existence of different affinity states of CCK 2 receptors suggested from the results of binding assays and behavioural studies.

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Section: Discussionmentioning

confidence: 99%

Further evidence that the CCK₂ receptor is coupled to two transduction pathways using site‐directed mutagenesis

Pommier

Marie-Claire

Nascimento

et al. 2003

Journal of Neurochemistry

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“…One disease-causing mutation in EDNRB has been linked to a selective loss of Gα q /Gα 11 coupling and intracellular Ca 2+ signaling (100, 161), while two others have been shown to perturb Gα i coupling and prevent the reduction in cAMP levels that occurs with Gα i activation (68). Of these possibilities, there is more evidence for EDNRB signaling through cAMP in ENCDCs.…”

Section: What Is the Function Of Ednrb In Ens Development?mentioning

confidence: 99%

Enteric nervous system development: migration, differentiation, and disease

Lake

Heuckeroth²

2013

American Journal of Physiology-Gastrointestinal and Liver Physi

296

225

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The enteric nervous system (ENS) provides the intrinsic innervation of the bowel and is the most neurochemically diverse branch of the peripheral nervous system, consisting of two layers of ganglia and fibers encircling the gastrointestinal tract. The ENS is vital for life and is capable of autonomous regulation of motility and secretion. Developmental studies in model organisms and genetic studies of the most common congenital disease of the ENS, Hirschsprung disease, have provided a detailed understanding of ENS development. The ENS originates in the neural crest, mostly from the vagal levels of the neuraxis, which invades, proliferates, and migrates within the intestinal wall until the entire bowel is colonized with enteric neural crest-derived cells (ENCDCs). After initial migration, the ENS develops further by responding to guidance factors and morphogens that pattern the bowel concentrically, differentiating into glia and neuronal subtypes and wiring together to form a functional nervous system. Molecules controlling this process, including glial cell line-derived neurotrophic factor and its receptor RET, endothelin (ET)-3 and its receptor endothelin receptor type B, and transcription factors such as SOX10 and PHOX2B, are required for ENS development in humans. Important areas of active investigation include mechanisms that guide ENCDC migration, the role and signals downstream of endothelin receptor type B, and control of differentiation, neurochemical coding, and axonal targeting. Recent work also focuses on disease treatment by exploring the natural role of ENS stem cells and investigating potential therapeutic uses. Disease prevention may also be possible by modifying the fetal microenvironment to reduce the penetrance of Hirschsprung disease-causing mutations.

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“…(G i , G o , and G s (16)), the endothelin subtype B receptor (G i , G o , and G q (17,18)). These different couplings suggest that GPCRs may exist in more than a single active state.…”

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confidence: 99%

Mutations in the Extracellular Amino-terminal Domain of the NK2 Neurokinin Receptor Abolish cAMP Signaling but Preserve Intracellular Calcium Responses

Lecat¹,

Bucher²,

Mély³

et al. 2002

Journal of Biological Chemistry

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G-protein-coupled receptors (GPCRs)1 represent the largest family of cell surface receptors and have multiple effects on the activated cell. Despite the variety of molecular types of ligands (hormones, proteins, small peptides, ions, lipids, and sensory stimuli such as odorants, pheromones, and photons), GPCRs share homology in their core domain composed of seven transmembrane ␣-helices. The conservation of the same overall hydrophobic structure exemplifies the essential role of this structure for the activation process.GPCR activation promotes GDP to GTP exchange on the ␣ subunit of the heterotrimeric G protein associated with its cytoplasmic loops, thereby initializing the intracellular cascade of signaling events. Among the theoretical models describing the activation mechanism, the two-state allosteric model of activation has been proposed, following the discovery of inverse agonists and of constitutive activity for GPCRs (1-4). In this model, a GPCR preexists in equilibrium between an active and an inactive state in the absence of ligand. As such, agonists, higher affinity for the active state having displace the equilibrium toward activation, whereas inverse agonists have higher affinities for the inactive state. Constitutive activity is explained by an intrinsic tendency for a receptor to spontaneously isomerize toward the active conformation. Although the multiple conformational states theory is an attractive model for describing GPCR activation, there is a need for more data correlating the parameters of possible intermediate conversion states with physiological responses.Indeed, several GPCRs have been reported to mediate multiple signaling pathways through activation of different heterotrimeric G proteins: the receptors for dopamine D1 (G s and G o (5), G s and G q (6)) and D5 (G s and G z (7)), the receptors for the parathyroid hormone (G s , G q , and G i (8)), for the corticotropinreleasing hormone (G s , G i , G q , G o , and G z (9)), for the melaninconcentrating hormone (G i and G o and maybe G q (10)), for the vasoactive intestinal peptide (G s and G i (11)), for prostacyclin (G s , G i , and G q (12)), the adenosine A1 receptor (G o and G i (13)), the ␤ 2 -adrenergic receptor (G s and G i (14)), the muscarinic m3 receptor (G q and G 12 (15)), the 5-hydroxytryptamine receptor type 4; Bpa, G o , and G s (16)), the endothelin subtype B receptor (G i , G o , and G q (17, 18)). These different couplings suggest that GPCRs may exist in more than a single active state.We have previously addressed the question of multiple receptor states by using fluorescence resonance energy transfer (FRET) to monitor ligand binding in parallel with cellular responses. A chimeric green fluorescent neurokinin NK2 receptor, EGFP-NK2R was expressed in HEK293 cells. Two of its neuropeptide agonists, the decapeptide neurokinin A (NKA) and its truncated form, NKA-(4 -10), were covalently linked to the fluorophore Texas Red (TR) (19). Kinetic measurements of the associations of TR1-NKA and TR7-NKA-(4 -10) to the EGFP-NK2 re...

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W276 Mutation in the Endothelin Receptor Subtype B Impairs G_q Coupling but Not G_i or G_o Coupling

Cited by 30 publications

References 32 publications

Further evidence that the CCK₂ receptor is coupled to two transduction pathways using site‐directed mutagenesis

Further evidence that the CCK₂ receptor is coupled to two transduction pathways using site‐directed mutagenesis

Enteric nervous system development: migration, differentiation, and disease

Mutations in the Extracellular Amino-terminal Domain of the NK2 Neurokinin Receptor Abolish cAMP Signaling but Preserve Intracellular Calcium Responses

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W276 Mutation in the Endothelin Receptor Subtype B Impairs Gq Coupling but Not Gi or Go Coupling

Cited by 30 publications

References 32 publications

Further evidence that the CCK2 receptor is coupled to two transduction pathways using site‐directed mutagenesis

Further evidence that the CCK2 receptor is coupled to two transduction pathways using site‐directed mutagenesis

Enteric nervous system development: migration, differentiation, and disease

Mutations in the Extracellular Amino-terminal Domain of the NK2 Neurokinin Receptor Abolish cAMP Signaling but Preserve Intracellular Calcium Responses

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W276 Mutation in the Endothelin Receptor Subtype B Impairs G_q Coupling but Not G_i or G_o Coupling

Further evidence that the CCK₂ receptor is coupled to two transduction pathways using site‐directed mutagenesis

Further evidence that the CCK₂ receptor is coupled to two transduction pathways using site‐directed mutagenesis