Arrestin Interactions with G Protein-coupled Receptors

Gurevich, Vsevolod V.; Dion, S.; Onorato, James J.; Ptasienski, J; Kim, Chong M.; Sterne‐Marr, Rachel; Hosey, M. Marlene; Benovic, Jeffrey L.

doi:10.1074/jbc.270.2.720

Cited by 366 publications

(298 citation statements)

References 47 publications

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“…Second, ET-R phosphorylation may be bridled by other intracellular proteins (particularly the arrestins), which may compete with even the high-affinity GRK(s) for receptor binding. In this regard, it is notable that phosphorylation of the receptor has been shown both to decrease the affinity of GRK binding (42) and to increase the affinity of arrestin isoform binding to the receptor (43).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation and Desensitization of Human Endothelin A and B Receptors

Freedman

Ament

Oppermann

et al. 1997

Journal of Biological Chemistry

174

160

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Although endothelin-1 can elicit prolonged physiologic responses, accumulating evidence suggests that rapid desensitization affects the primary G protein-coupled receptors mediating these responses, the endothelin A and B receptors (ET A -R and ET B -R). The mechanisms by which this desensitization proceeds remain obscure, however. Because some intracellular domain sequences of the ET A -R and ET B -R differ substantially, we tested the possibility that these receptor subtypes might be differentially regulated by G protein-coupled receptor kinases (GRKs). Homologous, or receptor-specific, desensitization occurred within 4 min both in the ET A -R-expressing A10 cells and in 293 cells transfected with either the human ET A -R or ET B -R. In 293 cells, this desensitization corresponded temporally with agonistinduced phosphorylation of each receptor, assessed by receptor immunoprecipitation from 32 P i -labeled cells. Agonist-induced receptor phosphorylation was not substantially affected by PKC inhibition but was reduced 40% (p < 0.03) by GRK inhibition, effected by a dominant negative GRK2 mutant. Inhibition of agonist-induced phosphorylation abrogated agonist-induced ET A -R desensitization. Overexpression of GRK2, -5, or -6 in 293 cells augmented agonist-induced ET-R phosphorylation ϳ2-fold (p < 0.02), but each kinase reduced receptorpromoted phosphoinositide hydrolysis differently. While GRK5 inhibited ET-R signaling by only ϳ25%, GRK2 inhibited ET-R signaling by 80% (p < 0.01). Congruent with its superior efficacy in suppressing ET-R signaling, GRK2, but not GRK5, co-immunoprecipitated with the ET-Rs in an agonist-dependent manner. We conclude that both the ET A -R and ET B -R can be regulated indistinguishably by GRK-initiated desensitization. We propose that because of its affinity for ET-Rs demonstrated by co-immunoprecipitation, GRK2 is the most likely of the GRKs to initiate ET-R desensitization.A variety of vital cardiovascular and developmental functions are mediated through the G protein 1 -coupled, heptahelical endothelin A and endothelin B receptors (ET A -R and ET B -R) (1, 2). Like many G protein-coupled receptor signaling systems (3), the receptor/G q /phospholipase C system(s) activated by the ET A -R and ET B -R have demonstrated diminishing responsiveness to prolonged stimulation (4 -11). This desensitization may be particularly important in the regulation of ET-R-mediated signaling, since endothelins bind their receptors essentially irreversibly under physiological conditions (2). In several cell types or tissues, this desensitization has been characterized phenomenologically as homologous, or receptorspecific (5-11), but the molecular mechanisms effecting this desensitization remain to be elucidated.For a growing number of G protein-coupled receptor signaling systems, phosphorylation of the receptor on serine and threonine residues appears to be an important mechanism of desensitization (3, 12). This phosphorylation can be accomplished by at least two classes of protein kinases: (i) second me...

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Section: Discussionmentioning

confidence: 99%

Phosphorylation and Desensitization of Human Endothelin A and B Receptors

Freedman

Ament

Oppermann

et al. 1997

Journal of Biological Chemistry

174

160

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“…R2 comprises 60-85 residues and functions as a regulatory domain that interacts with R1. Modified from [108] with the permission of the publishers.…”

Section: Figure 5 Molecular Architecture Of Arrestinsmentioning

confidence: 99%

“…There are several conserved domains that may be important for receptor recognition, binding and intramolecular reactions ( Figure 5). These domains have been characterized by mutagenesis and generation of chimaeric molecules [107][108][109].…”

Section: Arrestin Familiesmentioning

confidence: 99%

Regulatory mechanisms that modulate signalling by G-protein-coupled receptors

Böhm

Grady

Bunnett

1997

Biochemical Journal

476

322

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The large and functionally diverse group of G-protein-coupled receptors includes receptors for many different signalling molecules, including peptide and non-peptide hormones and neurotransmitters, chemokines, prostanoids and proteinases. Their principal function is to transmit information about the extracellular environment to the interior of the cell by interacting with the heterotrimeric G-proteins, and they thereby participate in many aspects of regulation. Cellular responses to agonists of these receptors are usually rapidly attenuated. Mechanisms of signal attenuation include removal of agonists from the extracellular fluid, receptor desensitization, endocytosis and downregulation. Agonists are removed by dilution, uptake by transporters and enzymic degradation. Receptor desensitization is mediated by receptor phosphorylation by G-protein receptor kinases and second-messenger kinases, interaction of phosphorylated receptors with arrestins and receptor uncoupling from

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“…However, it is important to note that the effect of phosphorylation often does not result in an "all or none binding phenomenon." For example, the effect of phosphorylation of receptors on the affinity for arrestin is only ϳ5-10-fold (43,44). Although this study as described above is primarily a horizontal analysis of the receptor tail library, a few vertical experiments were included to substantiate the results.…”

Section: Tm Receptor Tails and Post-endocytic Adaptor Proteinsmentioning

confidence: 99%

A Library of 7TM Receptor C-terminal Tails

Heydorn

Søndergaard

Ersbøll

et al. 2004

Journal of Biological Chemistry

146

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Adaptor and scaffolding proteins determine the cellular targeting, the spatial, and thereby the functional association of G protein-coupled seven-transmembrane receptors with co-receptors, transducers, and downstream effectors and the adaptors determine post-signaling events such as receptor sequestration through interactions, mainly with the C-terminal intracellular tails of the receptors. A library of tails from 59 representative members of the super family of seven-transmembrane receptors was probed as glutathione S-transferase fusion proteins for interactions with four different adaptor proteins previously proposed to be involved in postendocytotic sorting of receptors. Of the two proteins suggested to target receptors for recycling to the cell membrane, which is the route believed to be taken by a majority of receptors, ERM (ezrin-radixin-moesin)-binding phosphoprotein 50 (EBP50) bound only a single receptor tail, i.e. the ␤ 2 -adrenergic receptor, whereas N-ethylmaleimide-sensitive factor bound 11 of the tailfusion proteins. Of the two proteins proposed to target receptors for lysosomal degradation, sorting nexin 1 (SNX1) bound 10 and the C-terminal domain of G proteincoupled receptor-associated sorting protein bound 23 of the 59 tail proteins. Surface plasmon resonance analysis of the binding kinetics of selected hits from the glutathione S-transferase pull-down experiments, i.e. the tails of the virally encoded receptor US28 and the ␦-opioid receptor, confirmed the expected nanomolar affinities for interaction with SNX1. Truncations of the NK 1 receptor revealed that an extended binding epitope is responsible for the interaction with both SNX1 and G protein-coupled receptor-associated sorting protein as well as with Nethylmaleimide-sensitive factor. It is concluded that the tail library provides useful information on the general importance of certain adaptor proteins, for example, in this case, ruling out EBP50 as being a broad spectrumrecycling adaptor.Interaction of receptors with adaptor and scaffolding proteins is important for their biogenesis, their cellular sorting and targeting to the cell membrane, and their function at the membrane in complex with transducer molecules and downstream effector molecules as well as the subsequent internalization and post-endocytotic sorting of the receptors (1, 2). These interactions among receptors, adaptors, and scaffolding proteins are highly regulated processes that can be controlled by phosphorylation events (3), expression of receptor activating, or inactivating variants of adaptor proteins (4), by competition among adaptor proteins, and by competition between adaptor proteins and effector molecules (5). For the large family of G protein-coupled seven-transmembrane segment receptors (7TM 1 receptors), this field is still in its infancy and only a rather sketchy picture has emerged of relative importance of specific adaptor and scaffolding proteins for the biogenesis, function, and desensitization of these receptors. Methods such as yeast two-hybrid screening...

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Arrestin Interactions with G Protein-coupled Receptors

Cited by 366 publications

References 47 publications

Phosphorylation and Desensitization of Human Endothelin A and B Receptors

Phosphorylation and Desensitization of Human Endothelin A and B Receptors

Regulatory mechanisms that modulate signalling by G-protein-coupled receptors

A Library of 7TM Receptor C-terminal Tails

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