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Robert J Lefkowitz - One of the best experts on this subject based on the ideXlab platform.
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ReGulation of G Protein–Coupled Receptor SiGnalinG by Scaffold Proteins
Circulation Research, 2002Co-Authors: Randy A. Hall, Robert J LefkowitzAbstract:The actions of many hormones and neurotransmitters are mediated throuGh stimulation of G Protein–coupled receptors. A primary mechanism by which these receptors exert effects inside the cell is by association with heterotrimeric G Proteins, which can activate a wide variety of cellular enzymes and ion channels. G Protein–coupled receptors can also interact with a number of cytoplasmic scaffold Proteins, which can link the receptors to various siGnalinG intermediates and intracellular effectors. The multicomponent nature of G Protein–coupled receptor siGnalinG pathways makes them ideally suited for reGulation by scaffold Proteins. This review focuses on several specific examples of G Protein–coupled receptor-associated scaffolds and the roles they may play in orGanizinG receptor-initiated siGnalinG pathways in the cardiovascular system and other tissues.
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Endocytosis of G Protein-coupled receptors: roles of G Protein-coupled receptor kinases and ß-arrestin Proteins
Progress in Neurobiology, 2002Co-Authors: Audrey Claing, Stéphane A. Laporte, Marc G Caron, Robert J LefkowitzAbstract:Abstract Sequestration of G Protein-coupled receptors from the cell surface is a commonly observed phenomenon followinG aGonist-stimulation. This process is now believed to be important for receptor resensitization as well as for siGnal transduction. Over the years, numerous studies have aimed at understandinG the molecular mechanisms underlyinG internalization. Proteins such as the G Protein-coupled receptor kinases (GRKs) and the s-arrestins, which were initially characterized as desensitizinG molecules, have been shown to be important reGulators of the endocytic process. Recently, numerous interactinG partners have been identified for each of these two classes of Proteins. However, the details reGardinG the sequence of these interactions and the cross-talk between siGnalinG pathways containinG the different Protein complexes are just beGinninG to be uncovered. In this review, we summarize these findinGs and discuss the role of GRKs and s-arrestins, two families of key reGulatory Proteins that reGulate G Protein-coupled receptor endocytosis.
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G Protein coupled receptor kinases
Annual Review of Biochemistry, 1998Co-Authors: Julie A Pitcher, Neil J. Freedman, Robert J LefkowitzAbstract:G Protein-coupled receptor kinases (GRKs) constitute a family of six mammalian serine/threonine Protein kinases that phosphorylate aGonist-bound, or activated, G Protein-coupled receptors (GPCRs) as their primary substrates. GRK-mediated receptor phosphorylation rapidly initiates profound impairment of receptor siGnalinG, or desensitization. This review focuses on the reGulation of GRK activity by a variety of allosteric and other factors: aGonist-stimulated GPCRs, beta Gamma subunits of heterotrimeric GTP-bindinG Proteins, phospholipid cofactors, the calcium-bindinG Proteins calmodulin and recoverin, posttranslational isoprenylation and palmitoylation, autophosphorylation, and Protein kinase C-mediated GRK phosphorylation. Studies employinG recombinant, purified Proteins, cell culture, and transGenic animal models attest to the General importance of GRKs in reGulatinG a vast array of GPCRs both in vitro and in vivo.
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Molecular mechanisms of G Protein-coupled receptor siGnalinG: role of G Protein-coupled receptor kinases and arrestins in receptor desensitization and resensitization.
Receptors & Channels, 1997Co-Authors: Jie Zhang, Stephen S. Ferguson, M. J. Aber, Larry S Barak, Bruno Giros, Robert J Lefkowitz, Marc G CaronAbstract:Abstract Dynamic reGulation of G Protein-coupled receptor siGnalinG demands a coordinated balance between mechanisms leadinG to the Generation, turninG off and re-establishment of aGonist-mediated siGnals. G Protein-coupled receptor kinases (GRKs) and arrestin Proteins not only mediate aGonist-dependent G Protein-coupled receptor desensitization, but also initiate the internalization (sequestration) of activated receptors, a process leadinG to receptor resensitization. Studies on the specificity of beta-arrestin functions reveal a multiplicity of G Protein-coupled receptor endocytic pathways and suGGest that beta-arrestins miGht serve as adaptors specifically tarGetinG receptors for dynamin-dependent clathrin-mediated endocytosis. Moreover, inactivation of the GRK2 Gene in mice has lead to the discovery of an unexpected role of GRK2 in cardiac development, further emphasizinG the pleiotropic function of GRKs and arrestins.
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Desensitization of G Protein-coupled receptors.
Recent Progress in Hormone Research, 1996Co-Authors: Neil J. Freedman, Robert J LefkowitzAbstract:: WaninG responsiveness to continuous or repeated stimulation constitutes the phenomenon of desensitization, which pervades bioloGical systems. Over the last several years, molecular mechanisms for desensitization of cellular siGnalinG throuGh G Protein-coupled receptors have been delineated, particularly at the level of the receptors themselves. This review focuses on those aspects of G Protein-coupled receptor desensitization which occur within minutes of aGonist exposure. AGonist-dependent desensitization of these receptors can reduce their siGnalinG responsiveness to maximum stimulation by up to 70-80%; indeed, in some receptor systems, the process of receptor desensitization appears to effect the termination of the cellular siGnalinG response. AGonist-induced desensitization involves phosphorylation of G Protein-coupled receptors by two currently recoGnized classes of serine/threonine Protein kinases. Second messenGer-dependent kinases, phosphorylatinG a variety of Proteins, mediate a Generalized cellular hyporesponsiveness termed heteroloGous desensitization. G Protein-coupled receptor kinases (GRKs) phosphorylate specifically aGonist-occupied, or activated, receptors, and thereby initiate receptor-specific, or homoloGous, desensitization. GRK-mediated receptor phosphorylation facilitates the bindinG of an inhibitory arrestin Protein to the phosphorylated receptor, an event which substantially impairs receptor siGnalinG. The GRK family comprises six, and the arrestin family comprises four known members. Each GRK demonstrates the ability to phosphorylate a limited number of model receptor substrates, but the widespread expression of several GRKs and the two somatic arrestins suGGest that GRK-initiated homoloGous desensitization is of General importance to a wide ranGe of G Protein-coupled receptors. Exploration of the substrate specificity for GRKs and the liGand specificity for arrestins remains in its early staGes. Currently, GRKs can most readily be differentiated by the mechanisms each employs to associate with the plasma membrane. AccumulatinG data from human disease states and transGenic mice attest to the physioloGic siGnificance of GRK-initiated receptor desensitization.
Jeffrey L. Benovic - One of the best experts on this subject based on the ideXlab platform.
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β-Arrestins and G Protein-coupled receptor traffickinG.
Methods in Enzymology, 2013Co-Authors: Dong Soo Kang, Xufan Tian, Jeffrey L. BenovicAbstract:Arrestins are adaptor Proteins that function to reGulate G Protein-coupled receptor (GPCR) siGnalinG and traffickinG. There are four mammalian members of the arrestin family, two visual and two nonvisual. The visual arrestins (arrestin-1 and arrestin-4) are localized in rod and cone cells, respectively, and function to quench phototransduction by inhibitinG receptor/G Protein couplinG. The nonvisual arrestins (β-arrestin1 and β-arrestin2, a.k.a. arrestin-2 and arrestin-3) are ubiquitously expressed and function to inhibit GPCR/G Protein couplinG and promote GPCR traffickinG and arrestin-mediated siGnalinG. Arrestin-mediated endocytosis of GPCRs requires the coordinated interaction of β-arrestins with clathrin, adaptor Protein 2, and phosphoinositides such as PIP2/PIP3. These interactions are facilitated by a conformational chanGe in β-arrestin that is thouGht to occur upon bindinG to a phosphorylated activated GPCR. In this chapter, we provide an overview of the reaGents and techniques used to study β-arrestin-mediated receptor traffickinG.
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G-Protein-Coupled Receptors SiGnal Victory
Cell, 2012Co-Authors: Jeffrey L. BenovicAbstract:The 2012 Nobel Prize in Chemistry has been awarded to Brian K. Kobilka and Robert J. Lefkowitz for their studies of G-Protein-coupled receptors. Their pioneerinG work over the past 40 years has provided detailed molecular insiGht into the structure and function of this fundamentally important family of receptors.
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ReGulation of G Protein-coupled receptor kinases.
Trends in Cardiovascular Medicine, 2000Co-Authors: Raymond B. Penn, Alexey Pronin, Jeffrey L. BenovicAbstract:Abstract G Protein-coupled receptor kinases (GRKs) specifically interact with the aGonist-activated form of G Protein-coupled receptors (GPCRs) to effect receptor phosphorylation and desensitization. Recent studies demonstrate that GRK function is a hiGhly reGulated process, and it is perhaps in this manner that a handful of GRKs (7 have been identified to date) are able to reGulate the responsiveness of numerous GPCRs in a Given cell type in a coordinated manner. The mechanisms by which GRK activity is reGulated can be divided into 3 cateGories: 1) subcellular localization; 2) alterations in intrinsic kinase activity; and 3) alterations in GRK expression levels. This review will summarize our current understandinG of each of these reGulatory processes, and offer explanations as to how such mechanisms influence GPCR reGulation under various physioloGic conditions.
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G-Protein-coupled receptors: turn-ons and turn-offs
Current Opinion in Neurobiology, 1998Co-Authors: Christopher V. Carman, Jeffrey L. BenovicAbstract:Abstract Advances in the study of G-Protein-coupled receptor reGulation have provided novel insiGhts into the role of G-Protein-coupled receptor kinases and arrestins in this process. Of particular interest are recent studies that have dramatically expanded the known cellular functions of these molecules to include roles in receptor endocytosis and activation of MAP kinase siGnallinG pathways.
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ReGulation of G Protein Coupled Receptors
1997Co-Authors: Raymond B. Penn, Jeffrey L. BenovicAbstract:The sections in this article are: 1 SiGnalinG Via G Protein–Coupled Receptor Pathways 1.1 G Protein–Coupled Receptors 1.2 G Proteins 1.3 Effectors 2 Mechanisms of G Protein–Coupled Receptor ReGulation 2.1 Classification of Desensitization 2.2 The Beta-AdrenerGic Receptor and Rhodopsin SiGnalinG Pathways: Model Systems of GPR SiGnalinG and ReGulation 2.3 Receptor Phosphorylation And UncouplinG: Rapid Desensitization 2.4 Receptor Sequestration 2.5 Receptor Down-ReGulation 2.6 Receptor Polymorphisms 2.7 Sensitization 2.8 Desensitization of Other GPR Pathways 3 Summary
Graeme Milligan - One of the best experts on this subject based on the ideXlab platform.
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G-Protein-Coupled Receptor Dimers - G-Protein-Coupled Receptor Dimers
2017Co-Authors: Katharine Herrick-davis, Graeme Milligan, Giuseppe Di GiovanniAbstract:G-Protein-coupled receptors (GPCRs) are believed to be the larGest family of membrane Proteins involved in siGnal transduction and cellular responses. They dimerize (form a pair of macromolecules) with a wide variety of other receptors. The proposed book will provide a comprehensive overview of GPCR dimers, startinG with a historical perspective and includinG, basic information about the different dimers, how they synthesize, their siGnalinG properties, and the many diverse physioloGical processes in which they are involved. In addition to presentinG information about healthy GPCR dimer activity, the book will also include a section on their patholoGy and therapeutic potentials.
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A day in the life of a G Protein‐coupled receptor: the contribution to function of G Protein‐coupled receptor dimerization
British Journal of Pharmacology, 2009Co-Authors: Graeme MilliganAbstract:G Protein-coupled receptors are one of the most actively studied families of Proteins. However, despite the ubiquity of Protein dimerization and oliGomerization as a structural and functional motif in bioloGy, until the last decade they were Generally considered as monomeric, non-interactinG polypeptides. For the metabotropic Glutamate-like Group of G Protein-coupled receptors, it is now firmly established that they exist and function as dimers or, potentially, even within hiGher-order structures. Despite some evidence continuinG to support the view that rhodopsin-like G Protein-coupled receptors are predominantly monomers, many recent studies are consistent with the dimerization/oliGomerization of such receptors. Key roles suGGested for dimerization of G Protein-coupled receptors include control of Protein maturation and cell surface delivery and providinG the correct framework for interactions with both hetero-trimeric G Proteins and arrestins to allow siGnal Generation and its termination. As G Protein-coupled receptors are the most tarGeted Group of Proteins for the development of therapeutic small molecule medicines, recent indications that hetero-dimerization between co-expressed G Protein-coupled receptors may be a common process offers the potential for the development of more selective and tissue restricted medicines. However, many of the key experiments have, so far, been limited to model cell systems. Priorities for the future include the Generation of tools and reaGents able to identify unequivocally potential G Protein-coupled receptor hetero-dimers in native tissues and detailed analyses of the influence of hetero-dimerization on receptor function and pharmacoloGy.
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A day in the life of a G Protein-coupled receptor: the contribution to function of G Protein-coupled receptor dimerization.
British journal of pharmacology, 2007Co-Authors: Graeme MilliganAbstract:G Protein-coupled receptors are one of the most actively studied families of Proteins. However, despite the ubiquity of Protein dimerization and oliGomerization as a structural and functional motif in bioloGy, until the last decade they were Generally considered as monomeric, non-interactinG polypeptides. For the metabotropic Glutamate-like Group of G Protein-coupled receptors, it is now firmly established that they exist and function as dimers or, potentially, even within hiGher-order structures. Despite some evidence continuinG to support the view that rhodopsin-like G Protein-coupled receptors are predominantly monomers, many recent studies are consistent with the dimerization/oliGomerization of such receptors. Key roles suGGested for dimerization of G Protein-coupled receptors include control of Protein maturation and cell surface delivery and providinG the correct framework for interactions with both hetero-trimeric G Proteins and arrestins to allow siGnal Generation and its termination. As G Protein-coupled receptors are the most tarGeted Group of Proteins for the development of therapeutic small molecule medicines, recent indications that hetero-dimerization between co-expressed G Protein-coupled receptors may be a common process offers the potential for the development of more selective and tissue restricted medicines. However, many of the key experiments have, so far, been limited to model cell systems. Priorities for the future include the Generation of tools and reaGents able to identify unequivocally potential G Protein-coupled receptor hetero-dimers in native tissues and detailed analyses of the influence of hetero-dimerization on receptor function and pharmacoloGy.
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interactions between G Protein coupled receptors and periplakin a selective means to reGulate G Protein activation
Biochemical Society Transactions, 2004Co-Authors: Graeme Milligan, Elaine Kellett, Julia H White, Hannah Murdoch, Guijie FengAbstract:A substantial number of G-Protein-coupled receptor-interactinG Proteins have been identified initially by the use of yeast two-hybrid screens. UsinG the C-terminal tail of both opioid receptors and the melanin concentratinG hormone receptor-1 as bait, the actin and intermediate filament-bindinG Protein periplakin was isolated. In each case, the site of interaction is within helix VIII of the receptor and periplakin limits aGonist-mediated G-Protein activation potentially by competinG with G-Protein for this reGion of the receptor.
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Protein-Protein interactions at G-Protein-coupled receptors.
Trends in Pharmacological Sciences, 2001Co-Authors: Graeme Milligan, Julia H WhiteAbstract:The basic module of siGnal transduction that involves G-Protein-coupled receptors is usually portrayed as comprisinG a receptor, a heterotrimeric G Protein and an effector. It is now well established that reGulated interactions between receptors and arrestins, and between G Proteins and reGulators of G-Protein siGnallinG alter the effectiveness and kinetics of information transfer. However, more recent studies have beGun to identify a host of other Proteins that interact selectively with individual receptors at both the intracellular and extracellular face of the membrane. AlthouGh the functional relevance of many of these interactions is only beGinninG to be understood, current information indicates that these interactions miGht determine receptor properties, such as cellular compartmentalization or siGnal selection, and can promote Protein scaffoldinG into complexes that inteGrate function.
Heidi E. Hamm - One of the best experts on this subject based on the ideXlab platform.
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Heterotrimeric G Protein activation by G-Protein-coupled receptors
Nature Reviews Molecular Cell Biology, 2008Co-Authors: William M. Oldham, Heidi E. HammAbstract:Heterotrimeric G Proteins have a crucial role as molecular switches in siGnal transduction pathways mediated by G-Protein-coupled receptors. Extracellular stimuli activate these receptors, which then catalyse GTP–GDP exchanGe on the G Protein α-subunit. The complex series of interactions and conformational chanGes that connect aGonist bindinG to G Protein activation raise various interestinG questions about the structure, biomechanics, kinetics and specificity of siGnal transduction across the plasma membrane. G-Protein-coupled receptors (GPCRs) represent one of the larGest and most diverse Groups of Proteins in the Genome. Activated receptors catalyse nucleotide exchanGe on a relatively small Group of heterotrimeric G Proteins to initiate intracellular siGnallinG. Biophysical studies of rhodopsin-family GPCRs have shown that receptor activation results in an outward movement of transmembrane helix VI, which opens a pocket for G Protein bindinG. IncreasinG evidence suGGests that the structure, conformation and specificity of the G Protein bindinG site can be reGulated by the identity of the bound liGand. Several different models for receptor–G-Protein association have been proposed. These Proteins may be precoupled in a larGe siGnallinG complex. Nucleotide exchanGe may follow a series of transition complexes. Receptors may function as dimers to activate G Proteins. Biophysical studies indicate that receptor-mediated GDP release requires a conformational chanGe in the α5 helix of the Gα subunit and is associated with structural chanGes at the Gβ bindinG site. However, additional studies are required to fully describe the mechanism of receptor-mediated GDP release and the structure of the receptor–G-Protein complex. BindinG of GTP induces a structural rearranGement of the receptor–G-Protein complex that leads to dissociation of some, but not all, complexes. This observation is consistent with the existence of precoupled receptor–G-Protein complexes that may not completely disassemble on G Protein activation. Fundamentally, the unanswered questions about G Protein activation reflect a poor understandinG of the structure of the complex. A Goal of future studies will be to refine current models of the receptor–G-Protein complex in terms of the available structural information until a crystal structure of the complex is solved. Extracellular siGnals can be transduced across the plasma membrane by activatinG G-Protein-coupled receptors. The conformational chanGes induced in the receptor on liGand bindinG and how this causes the activation of the associated G Protein are beGinninG to be understood.
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heterotrimeric G Protein activation by G Protein coupled receptors
Nature Reviews Molecular Cell Biology, 2008Co-Authors: William M. Oldham, Heidi E. HammAbstract:Heterotrimeric G Proteins have a crucial role as molecular switches in siGnal transduction pathways mediated by G-Protein-coupled receptors. Extracellular stimuli activate these receptors, which then catalyse GTP-GDP exchanGe on the G Protein alpha-subunit. The complex series of interactions and conformational chanGes that connect aGonist bindinG to G Protein activation raise various interestinG questions about the structure, biomechanics, kinetics and specificity of siGnal transduction across the plasma membrane.
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Interaction of rhodopsin with the G-Protein, transducin.
BioEssays, 2005Co-Authors: Paul A. Hargrave, Heidi E. Hamm, K. P. HofmannAbstract:: Rhodopsin, upon activation by liGht, transduces the photon siGnal by activation of the G-Protein, transducin. The well-studied rhodopsin/transducin system serves as a model for the understandinG of siGnal transduction by the larGe class of G-Protein-coupled receptors. The interactive form of rhodopsin, R*, is conformationally similar or identical to rhodopsin's photolysis intermediate Metarhodopsin II (MII). Formation of MII requires deprotonation of rhodopsin's protonated Schiff base which appears to facilitate some openinG of the rhodopsin structure. This allows a chanGe in conformation at rhodopsin's cytoplasmic surface that provides bindinG sites for transducin. Rhodopsin's 2nd, 3rd and putative 4th cytoplasmic loops bind transducin at sites includinG transducin's 5 kDa carboxyl-terminal reGion. Site-specific mutaGenesis of rhodopsin is beinG used to distinGuish sites on rhodopsin's surface that are important in bindinG transducin from those that function in activatinG transducin. These observations are consistent with and extend studies on the action of other G-Protein-coupled receptors and their interactions with their respective G Proteins.
Marc G Caron - One of the best experts on this subject based on the ideXlab platform.
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Endocytosis of G Protein-coupled receptors: roles of G Protein-coupled receptor kinases and ß-arrestin Proteins
Progress in Neurobiology, 2002Co-Authors: Audrey Claing, Stéphane A. Laporte, Marc G Caron, Robert J LefkowitzAbstract:Abstract Sequestration of G Protein-coupled receptors from the cell surface is a commonly observed phenomenon followinG aGonist-stimulation. This process is now believed to be important for receptor resensitization as well as for siGnal transduction. Over the years, numerous studies have aimed at understandinG the molecular mechanisms underlyinG internalization. Proteins such as the G Protein-coupled receptor kinases (GRKs) and the s-arrestins, which were initially characterized as desensitizinG molecules, have been shown to be important reGulators of the endocytic process. Recently, numerous interactinG partners have been identified for each of these two classes of Proteins. However, the details reGardinG the sequence of these interactions and the cross-talk between siGnalinG pathways containinG the different Protein complexes are just beGinninG to be uncovered. In this review, we summarize these findinGs and discuss the role of GRKs and s-arrestins, two families of key reGulatory Proteins that reGulate G Protein-coupled receptor endocytosis.
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G Protein-coupled receptor adaptation mechanisms.
Seminars in Cell & Developmental Biology, 1998Co-Authors: Stephen S G Ferguson, Marc G CaronAbstract:Abstract G Protein-coupled receptors (GPCRs) transduce extracellular siGnals that modulate the activity of a wide variety of bioloGical processes, such as neurotransmission, chemoattraction, cardiac function, olfaction, and vision. However, GPCR siGnallinG desensitizes rapidly as the consequence of receptor phosphorylation. G Protein-coupled receptor kinase-mediated receptor phosphorylation promotes the bindinG of β-arrestin Proteins, which not only uncouple GPCRs from their coGnate heterotrimeric G Protein, but also tarGet them for endocytosis. The sequestration (endocytosis) of desensitized GPCRs to endosomes is required for their dephosphorylation and subsequent resensitization to their pre-liGand exposed state. This review concentrates on the mechanisms underlyinG GPCR desensitization and resensitization.
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Molecular mechanisms of G Protein-coupled receptor siGnalinG: role of G Protein-coupled receptor kinases and arrestins in receptor desensitization and resensitization.
Receptors & Channels, 1997Co-Authors: Jie Zhang, Stephen S. Ferguson, M. J. Aber, Larry S Barak, Bruno Giros, Robert J Lefkowitz, Marc G CaronAbstract:Abstract Dynamic reGulation of G Protein-coupled receptor siGnalinG demands a coordinated balance between mechanisms leadinG to the Generation, turninG off and re-establishment of aGonist-mediated siGnals. G Protein-coupled receptor kinases (GRKs) and arrestin Proteins not only mediate aGonist-dependent G Protein-coupled receptor desensitization, but also initiate the internalization (sequestration) of activated receptors, a process leadinG to receptor resensitization. Studies on the specificity of beta-arrestin functions reveal a multiplicity of G Protein-coupled receptor endocytic pathways and suGGest that beta-arrestins miGht serve as adaptors specifically tarGetinG receptors for dynamin-dependent clathrin-mediated endocytosis. Moreover, inactivation of the GRK2 Gene in mice has lead to the discovery of an unexpected role of GRK2 in cardiac development, further emphasizinG the pleiotropic function of GRKs and arrestins.
