Exploring functional consequences of GPCR oligomerization requires a different lens

Bourque, Kyla; Jones-Tabah, Jace; Devost, Dominic; Clarke, Paul B. S.; Hébert, Terence E.

doi:10.1016/bs.pmbts.2019.11.001

Cited by 12 publications

(14 citation statements)

References 94 publications

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“…In agreement with previous studies on other GPCRs [25,[59][60][61], changes in BRET signals induced by agonists or inverse agonists strongly suggest the existence of allosteric cross-talks between the two H 3 R protomers. In agreement, a previous study established that GPCRs of Class A, to which the H 3 R belongs [62], operate through the transactivation between the two protomers [8,26]. As reported for the GABAB receptor [63], maximal activation of dimers was ensured by agonist binding to a single protomer.…”

Section: Discussionsupporting

confidence: 90%

“…A large body of biochemical and biophysical evidence indicates that G-protein-coupled receptors (GPCRs) form dimers not only in heterologous systems but also in native tissues [ 1 , 2 , 3 , 4 , 5 , 6 ]. The observation that GPCRs can form dimers or larger oligomers has led to intense research to study the functional and physiological relevance of such complex formations [ 7 , 8 , 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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BRET Analysis of GPCR Dimers in Neurons and Non-Neuronal Cells: Evidence for Inactive, Agonist, and Constitutive Conformations

Khamlichi

Cobret

Arrang

et al. 2021

IJMS

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G-protein-coupled receptors (GPCRs) are dimeric proteins, but the functional consequences of the process are still debated. Active GPCR conformations are promoted either by agonists or constitutive activity. Inverse agonists decrease constitutive activity by promoting inactive conformations. The histamine H3 receptor (H3R) is the target of choice for the study of GPCRs because it displays high constitutive activity. Here, we study the dimerization of recombinant and brain H3R and explore the effects of H3R ligands of different intrinsic efficacy on dimerization. Co-immunoprecipitations and Western blots showed that H3R dimers co-exist with monomers in transfected HEK 293 cells and in rodent brains. Bioluminescence energy transfer (BRET) analysis confirmed the existence of spontaneous H3R dimers, not only in living HEK 293 cells but also in transfected cortical neurons. In both cells, agonists and constitutive activity of the H3R decreased BRET signals, whereas inverse agonists and GTPγS, which promote inactive conformations, increased BRET signals. These findings show the existence of spontaneous H3R dimers not only in heterologous systems but also in native tissues, which are able to adopt a number of allosteric conformations, from more inactive to more active states.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

BRET Analysis of GPCR Dimers in Neurons and Non-Neuronal Cells: Evidence for Inactive, Agonist, and Constitutive Conformations

Khamlichi

Cobret

Arrang

et al. 2021

IJMS

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“…Over the last two decades, much evidence accumulated suggesting that GPCRs may also physically interact with each other and function as dimers or larger order oligomeric complexes [ 25 ]. Indirect evidence of GPCR interaction was initially provided by Limbird et al (1975) [ 26 ] for β-adrenergic receptors in frog erythrocyte membranes by a direct kinetic method.…”

Section: Dimerization Of Gpcrsmentioning

confidence: 99%

Integration and Spatial Organization of Signaling by G Protein-Coupled Receptor Homo- and Heterodimers

et al. 2021

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Information flow from a source to a receiver becomes informative when the recipient can process the signal into a meaningful form. Information exchange and interpretation is essential in biology and understanding how cells integrate signals from a variety of information-coding molecules into complex orchestrated responses is a major challenge for modern cell biology. In complex organisms, cell to cell communication occurs mostly through neurotransmitters and hormones, and receptors are responsible for signal recognition at the membrane level and information transduction inside the cell. The G protein-coupled receptors (GPCRs) are the largest family of membrane receptors, with nearly 800 genes coding for these proteins. The recognition that GPCRs may physically interact with each other has led to the hypothesis that their dimeric state can provide the framework for temporal coincidence in signaling pathways. Furthermore, the formation of GPCRs higher order oligomers provides the structural basis for organizing distinct cell compartments along the plasma membrane where confined increases in second messengers may be perceived and discriminated. Here, we summarize evidence that supports these conjectures, fostering new ideas about the physiological role played by receptor homo- and hetero-oligomerization in cell biology.

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“…GPCRs exist as homo-oligomers, in addition to interact with other receptors, forming hetero-oligomers, affecting in this way their functionality. Due to GPCR oligomerization, different properties such as synthesis, cell membrane diffusion, binding to the agonist, pharmacology, signaling, and trafficking may be altered (Milligan, 2010;Ferre et al, 2014;Gomes et al, 2016;Bourque et al, 2020). Due to GPCR oligomerization ligand affinity for its receptor may change.…”

Section: Mechanisms Of Gpcr Signaling Diversification Angiotensin Recmentioning

confidence: 99%

“…Receptor homomer and homomeric receptor would be, respectively, defined in the same way as receptor heteromer and heteromeric receptor but with the distinction of being formed by "two or more identical protomers or identical non-functional subunits" (Ferre et al, 2020). Heteromerization of receptors may result in alterations in their biosynthesis, plasma membrane diffusion rate, ligand binding, pharmacology, and signaling (Sleno and Hebert, 2018;Sposini and Hanyaloglu, 2018;Bourque et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Angiotensin Receptors Heterodimerization and Trafficking: How Much Do They Influence Their Biological Function?

et al. 2020

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G-protein-coupled receptors (GPCRs) are targets for around one third of currently approved and clinical prescribed drugs and represent the largest and most structurally diverse family of transmembrane signaling proteins, with almost 1000 members identified in the human genome. Upon agonist stimulation, GPCRs are internalized and trafficked inside the cell: they may be targeted to different organelles, recycled back to the plasma membrane or be degraded. Once inside the cell, the receptors may initiate other signaling pathways leading to different biological responses. GPCRs' biological function may also be influenced by interaction with other receptors. Thus, the ultimate cellular response may depend not only on the activation of the receptor from the cell membrane, but also from receptor trafficking and/or the interaction with other receptors. This review is focused on angiotensin receptors and how their biological function is influenced by trafficking and interaction with others receptors.

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Exploring functional consequences of GPCR oligomerization requires a different lens

Cited by 12 publications

References 94 publications

BRET Analysis of GPCR Dimers in Neurons and Non-Neuronal Cells: Evidence for Inactive, Agonist, and Constitutive Conformations

BRET Analysis of GPCR Dimers in Neurons and Non-Neuronal Cells: Evidence for Inactive, Agonist, and Constitutive Conformations

Integration and Spatial Organization of Signaling by G Protein-Coupled Receptor Homo- and Heterodimers

Angiotensin Receptors Heterodimerization and Trafficking: How Much Do They Influence Their Biological Function?

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