Visualizing differences in ligand‐induced β‐arrestin–GFP interactions and trafficking between three recently characterized G protein‐coupled receptors

Evans, Nina; Groarke, D. A.; Warrack, John; Greenwood, C. J.; Dodgson, K. S.; Milligan, Graeme; Wilson, Shelagh

doi:10.1046/j.1471-4159.2001.00269.x

Cited by 67 publications

(62 citation statements)

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“…Consistent with this assertion, the murine apelin receptor contains 14 serine or threonine residues in its C terminus (4), and the protein is rapidly internalized after ligand binding (27)(28)(29). To investigate the role of phosphorylation in desensitization, we constructed a truncated receptor, ⌬327-377, in which most serine/threonine residues were deleted, and analyzed its activation by apelin fragments.…”

Section: Regulation Of Intracellular Effectors By Apelin Fragments Anmentioning

confidence: 85%

“…Apelin Receptor Is Subject to Differential Desensitization by Apelin Fragments-Although internalization of the apelin receptor has been widely observed by the use of tagged receptors or fluorescent apelin-(65-77) (27)(28)(29), the only evidence of desensitization was that repeated exposure to apelin fragments resulted in a decrease of the calcium response in NT2.N neurons (10). In this study, we report interesting features of the differential effects induced by a preincubation with each fragment.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of apelin receptors by the short fragment is proposed to be transient and rapidly turned off by receptor internalization (27,28). The duration of desensitization would thus depend on the rate of receptor recycling to the plasma membrane (29).…”

Section: C-terminal Truncation Of the Receptor Does Not Modify The Dementioning

confidence: 99%

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The Apelin Receptor Is Coupled to Gi1 or Gi2 Protein and Is Differentially Desensitized by Apelin Fragments

Masri¹,

Morin

Pedebernade

et al. 2006

Journal of Biological Chemistry

139

113

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The apelin receptor is a G protein-coupled receptor to which two ligand fragments, apelin-(65-77) and apelin-(42-77), can bind. To address the physiological significance of the existence of dual ligands for a single receptor, we first compared the ability of the apelin fragments to regulate intracellular effectors, to promote G protein coupling, and to desensitize the response in Chinese hamster ovary cells expressing the murine apelin receptor. We found that both apelin fragments inhibited adenylyl cyclase and increased the phosphorylation of ERK or Akt. Using stably transfected cells expressing a pertussis toxin-insensitive ␣ i subunit, we demonstrated that each apelin fragment promoted coupling of the apelin receptor to either G␣ i1 or G␣ i2 but not to G␣ i3 . Although preincubation with each apelin fragment induced a desensitization at the level of the three effectors, preincubation with apelin-(42-77) also increased basal effector activity. In addition, a C-terminal deletion of the apelin receptor decreased the desensitization induced by apelin-(65-77) but did not alter the desensitization pattern induced by apelin-(42-77). Finally, in umbilical endothelial cells, which we have recently shown to express the apelin receptor, the G␣ i1 and G␣ i2 subunits are also expressed, ERK and Akt phosphorylation is desensitized after preincubation with apelin-(65-77), and basal levels of Akt phosphorylation are increased after preincubation with apelin-(42-77). In summary, apelin fragments regulate the same effectors, via the preferential coupling of the apelin receptor to G i1 or G i2 , but they promote a differential desensitization pattern that may be central to their respective physiological roles.The recently discovered apelin signaling pathway plays a role in the central and peripheral regulation of the cardiovascular system, in water and food intake, and possibly in immune function (for a review, see Ref.1). The apelin receptor was first identified in human (2) and amphibians (3), and the murine receptor was later cloned from embryonic tissues (4). The deduced protein sequence of these three orthologs revealed that the apelin receptor is a member of the G protein-coupled, seventransmembrane domain receptor family and displays a structural relationship with angiotensin receptors (2) and CXC chemokine receptors (3, 5). However, angiotensin II did not bind to it, and the receptor remained orphan until the identification of apelin, its endogenous ligand (6). Cloning of the apelin gene showed that it codes for a preproprotein of 77 residues containing a signal peptide, which, after proteolytic maturation, generates the apelin fragment of 36 amino acids, apelin-(42-77), first isolated from stomach extracts (6). Although the existence of several endogenous apelin fragments was inferred from the presence of conserved basic doublets in the protein sequence, their physiological occurrence has been validated by the characterization of two active peaks from stomach extracts (6) and by gel filtration chromatography of colostr...

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Section: Regulation Of Intracellular Effectors By Apelin Fragments Anmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Apelin Receptor Is Coupled to Gi1 or Gi2 Protein and Is Differentially Desensitized by Apelin Fragments

Masri¹,

Morin

Pedebernade

et al. 2006

Journal of Biological Chemistry

139

113

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“…The AR has been shown to internalize following association with β-arrestin (Evans et al 2001;Lee et al 2010) in a clathrin-dependent manner Said El Messari 2004). Interestingly, the stretch activated response of the AR mentioned previously is both β-arrestin-dependent and G-protein-independent (Scimia et al 2012).…”

Section: β-Arrestin-dependent Internalization and G-protein-independementioning

confidence: 89%

The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR

Chapman

Dupré

Rainey

2014

Biochem. Cell Biol.

171

135

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The apelin receptor (AR or APJ) is a class A (rhodopsin-like) G-protein coupled receptor (GPCR) with wide distribution throughout the human body. Activation of the AR by its cognate peptide ligand, apelin, induces diverse physiological effects including vasoconstriction and dilation; strengthening of heart muscle contractility; angiogenesis; and, regulation of energy metabolism and fluid homeostasis. Recently, another endogenous peptidic activator of the AR, Toddler/ ELABELA, was identified as having a crucial role in zebrafish embryonic development. The AR is also implicated in pathologies including cardiovascular disease, diabetes, obesity and cancer, making it a promising therapeutic target. Despite its established importance, the precise roles of AR signalling remain poorly understood. Moreover, little is known about mechanisms of peptide-AR activation. Additional complexity arises from modulation of the AR by two endogenous peptide ligands, both with multiple bioactive isoforms of variable length and distribution. The various apelin and Toddler/ELABELA isoforms may also produce distinct cellular effects. Further complexity arises through formation of functionally distinct heterodimers between the AR and other GPCRs. This minireview outlines key (patho)physiological actions of the AR, addresses what is known about signal transduction downstream of AR activation, and concludes by discussing unique properties of the endogenous peptidic ligands of the AR.

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“…After a 25 min incubation, 200 l aliquots of media from each well were added directly to scintillation vials for measurement of [ 3 H] content (AA release) with liquid scintillation counting. The remaining media was aspirated quickly, and 2 ml of 10 mM formic acid was added to extract the accumulated (Evans et al, 2001). Briefly, after 24 hr in serum-free media, cells in 15 cm plates (ϳ320 g of total protein) were washed twice with ice-cold HBSS, scraped, and pelleted.…”

Section: Methodsmentioning

confidence: 99%

Constitutive Activity of the Serotonin2C Receptor InhibitsIn VivoDopamine Release in the Rat Striatum and Nucleus Accumbens

Deurwaerdère¹,

Navailles²,

Berg³

et al. 2004

J. Neurosci.

287

235

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Numerous research has pointed out that serotonin2c (5-HT 2C ) receptor, a subtype of 5-HT receptors belonging to the G-protein-coupled receptor superfamily, modulates the activity of mesencephalic dopamine (DA) neurons, the dysfunction of which is involved in devastating diseases such as schizophrenia, Parkinson's disease, and drug addiction. In the present study, using in vivo intracerebral microdialysis and Chinese hamster ovary (CHO) cells expressing 5-HT 2C receptors to identify appropriate 5-HT 2C receptor ligands, we sought to determine whether the property of 5-HT 2C receptors to spontaneously activate intracellular signaling pathways in vitro (constitutive activity) participates in the tonic inhibitory control that they exert on DA release in the rat striatum and nucleus accumbens in vivo. In

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Visualizing differences in ligand‐induced β‐arrestin–GFP interactions and trafficking between three recently characterized G protein‐coupled receptors

Cited by 67 publications

References 50 publications

The Apelin Receptor Is Coupled to Gi1 or Gi2 Protein and Is Differentially Desensitized by Apelin Fragments

The Apelin Receptor Is Coupled to Gi1 or Gi2 Protein and Is Differentially Desensitized by Apelin Fragments

The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR

Constitutive Activity of the Serotonin2C Receptor InhibitsIn VivoDopamine Release in the Rat Striatum and Nucleus Accumbens

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