G-protein-coupled receptor kinases and arrestins: regulators of G-protein-coupled receptor sequestration

Ferguson, Stephen S. G.; Zhang, J.; Barak, Larry S.; Caron, Marc G.

doi:10.1042/bst0240953

Cited by 39 publications

(21 citation statements)

References 6 publications

(6 reference statements)

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“…1A). In 1996, Ferguson et al [26,27] found that overexpression of arrestin-2 potentiated agonist-mediated internalization of ␤2-adrenergic receptors. Additionally, a dominant-negative mutant of arrestin-2 attenuated agonist-induced internalization in transiently transfected HEK-293 cells [26].…”

Section: Role Of Arrestins In 5-ht 2a Desensitization and Internalizamentioning

confidence: 99%

Paradoxical trafficking and regulation of 5-HT2A receptors by agonists and antagonists

Gray

Roth

2001

Brain Research Bulletin

264

198

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Section: Role Of Arrestins In 5-ht 2a Desensitization and Internalizamentioning

confidence: 99%

Paradoxical trafficking and regulation of 5-HT2A receptors by agonists and antagonists

Gray

Roth

2001

Brain Research Bulletin

264

198

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“…In response to ligand binding, GPCRs are usually phosphorylated by G protein-coupled receptor kinases and often by kinases activated by downstream signals, such as protein kinase A and protein kinase C. TRH receptors undergo agonistinduced internalization through the clathrin-and dynaminmediated endocytotic pathway (49,66,67,69), presumably initiated by receptor phosphorylation and the subsequent interaction of phosphorylated receptors with ␤-arrestin, which targets receptors to clathrin-coated pits for endocytosis (68). Hanyaloglu et al (58) present intriguing data suggesting that phosphorylation of the TRH receptor by CKII is important for TRH-stimulated recruitment of ␤-arrestin.…”

Section: Expression Of Trh Receptors In Hek293mentioning

confidence: 99%

Dimerization and Phosphorylation of Thyrotropin-releasing Hormone Receptors Are Modulated by Agonist Stimulation

Zhu¹,

Cook

Hinkle

2002

Journal of Biological Chemistry

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Dimerization and phosphorylation of thyrotropin-releasing hormone (TRH) receptors was characterized using HEK293 and pituitary GHFT cells expressing epitope-tagged receptors. TRH receptors tagged with FLAG and hemagglutinin epitopes were co-precipitated only if they were co-expressed, and 10 -30% of receptors were isolated as hemagglutinin/FLAG-receptor dimers under basal conditions. The abundance of receptor dimers was increased when cells had been stimulated by TRH, indicating that TRH either stabilizes pre-existing dimers or increases dimer formation. TRH increased receptor dimerization and phosphorylation within 1 min in a dose-dependent manner. TRH increased phosphorylation of both receptor monomers and dimers, documented by incorporation of 32 P and an upshift in receptor mobility reversed by phosphatase treatment. The ability of TRH to increase receptor phosphorylation and dimerization did not depend on signal transduction, because it was not inhibited by the phospholipase C inhibitor U73122. Receptor phosphorylation required an agonist but was not blocked by the casein kinase II inhibitor apigenin, the protein kinase C inhibitor GF109203X, or expression of a dominant negative form of G protein-coupled receptor kinase 2. TRH receptors lacking most of the cytoplasmic carboxyl terminus formed dimers constitutively but failed to undergo agonist-induced dimerization and phosphorylation. TRH also increased phosphorylation and dimerization of TRH receptors expressed in GHFT pre-lactotroph cells.The TRH 1 receptor belongs to the superfamily of seventransmembrane-helix G protein-coupled receptors (GPCRs) and plays a key role in maintaining proper function of the thyroid gland (1, 2). Two subtypes of TRH receptors, termed type 1 and 2, have been identified (3-5). Although both receptor types are detected in various tissues at different levels (6 -8), the type 1 TRH receptor is primarily expressed in thyrotrophs and lactotrophs in the anterior pituitary gland, and its activation stimulates the secretion of TSH and prolactin, at least in part, by raising the intracellular calcium concentration (9, 10). The TRH receptor, once occupied by agonist, activates phospholipase C through G q/11 , leading to the formation of inositol 1,4,5-trisphosphate (InsP 3 ), which causes an elevation of intracellular calcium by mobilizing an InsP 3 -sensitive Ca 2ϩ store in the endoplasmic reticulum (10, 11).In conventional models, GPCRs have been thought to function as monomers that bind one molecule of ligand and then activate one heterotrimeric G protein to turn on the cognate signaling pathway (12-16). However, evidence indicating that GPCRs can form homo-or heterodimers, pairing with the same receptor type, different subtypes within the same receptor family, or even distinct classes of receptors, has begun to emerge. Receptor dimerization has been documented for a wide variety of GPCRs including the ␤ 2 -adrenergic receptor (17, 18), Ca 2ϩ -sensing receptor (19,20), muscarinic m3 receptor (21), ␥-aminobutyric acid GABA B receptor (...

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“…GRK-phosphorylated GPCRs bind stoichiometrically to inhibitory proteins known as arrestins. The binding of ␤-arrestin1 or -2, extraretinal isoforms, prevents receptor-mediated G protein activation, recruits other molecules such as Src to the receptor, and serves to target the phosphorylated receptor for internalization via clathrin-coated pits (2). The recruitment of Src and engagement of the clathrincoated pit system by the phosphorylated ␤ 2 -adrenergic receptor (␤ 2 AR) have been shown to be essential for ␤ 2 AR-mediated ERK activation (3).…”

mentioning

confidence: 99%

Feedback Inhibition of G Protein-coupled Receptor Kinase 2 (GRK2) Activity by Extracellular Signal-regulated Kinases

Pitcher¹,

Tesmer²,

Freeman³

et al. 1999

Journal of Biological Chemistry

167

144

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G protein-coupled receptor kinase (GRK)-mediated receptor phosphorylation and ␤-arrestin binding uncouple G protein-coupled receptors (GPCRs) from their respective G proteins and initiates the process of receptor internalization. In the case of the ␤ 2 -adrenergic receptor and lysophosphatidic acid receptor, these processes can lead to ERK activation. Here we identify a novel mechanism whereby the activity of GRK2 is regulated by feedback inhibition. GRK2 is demonstrated to be a phosphoprotein in cells. Mass spectrometry and mutational analysis localize the site of phosphorylation on GRK2 to a carboxyl-terminal serine residue (Ser 670 ). Phosphorylation at Ser 670 impairs the ability of GRK2 to phosphorylate both soluble and membrane-incorporated receptor substrates and dramatically attenuates G␤␥-mediated activation of this enzyme. Ser 670 is located in a peptide sequence that conforms to an ERK consensus phosphorylation sequence, and in vitro, in the presence of heparin, ERK1 phosphorylates GRK2. Inhibition of ERK activity in HEK293 cells potentiates GRK2 activity, whereas, conversely, ERK activation inhibits GRK2 activity. The discovery that ERK phosphorylates and inactivates GRK2 suggests that ERK participates in a feedback regulatory loop. By negatively regulating GRK-mediated receptor phosphorylation, ␤-arrestin-mediated processes such as Src recruitment and clathrin-mediated internalization, which are required for GPCR-mediated ERK activation, are inhibited, thus dampening further ERK activation.

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G-protein-coupled receptor kinases and arrestins: regulators of G-protein-coupled receptor sequestration

Cited by 39 publications

References 6 publications

Paradoxical trafficking and regulation of 5-HT2A receptors by agonists and antagonists

Paradoxical trafficking and regulation of 5-HT2A receptors by agonists and antagonists

Dimerization and Phosphorylation of Thyrotropin-releasing Hormone Receptors Are Modulated by Agonist Stimulation

Feedback Inhibition of G Protein-coupled Receptor Kinase 2 (GRK2) Activity by Extracellular Signal-regulated Kinases

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