The lipid phase preference of the adenosine A<sub>2A</sub> receptor depends on its ligand binding state

Gutierrez, M. Gertrude; Deyell, Jacob S; White, Kate L.; Ore, Lucia Caterina Dalle; Cherezov, Vadim; Stevens, Raymond C.; Malmstadt, Noah

doi:10.1039/c8cc10130b

Cited by 10 publications

(15 citation statements)

References 44 publications

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“…As alluded to above, a major shortcoming of our nanodisc system is the upper limit of cholesterol that can be delivered. This prevented us from evaluating the system at higher, more physiological cholesterol concentrations and probing the effects from protein partitioning between liquid ordered and liquid disordered phases ( Gutierrez et al, 2019 ). It is unclear whether A 2A R alone prefers certain regions on the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Allosteric modulation of the adenosine A2A receptor by cholesterol

Huang

Almurad

Pejana

et al. 2022

eLife

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Cholesterol is a major component of the cell membrane and commonly regulates membrane protein function. Here, we investigate how cholesterol modulates the conformational equilibria and signaling of the adenosine A2A receptor (A2AR) in reconstituted phospholipid nanodiscs. This model system conveniently excludes possible effects arising from cholesterol-induced phase separation or receptor oligomerization and focuses on the question of allostery. GTP hydrolysis assays show that cholesterol weakly enhances the basal signaling of A2AR while decreasing the agonist EC50. Fluorine nuclear magnetic resonance (19F NMR) spectroscopy shows that this enhancement arises from an increase in the receptor’s active state population and a G-protein-bound precoupled state. 19F NMR of fluorinated cholesterol analogs reveals transient interactions with A2AR, indicating a lack of high-affinity binding or direct allosteric modulation. The combined results suggest that the observed allosteric effects are largely indirect and originate from cholesterol-mediated changes in membrane properties, as shown by membrane fluidity measurements and high-pressure NMR.

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Section: Discussionmentioning

confidence: 99%

Allosteric modulation of the adenosine A2A receptor by cholesterol

Huang

Almurad

Pejana

et al. 2022

eLife

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“…The best studied member of the family is rhodopsin, for which NMR (Soubias & Gawrisch, 2005;Soubias & Gawrisch, 2012;Soubias et al, 2008;Feller et al, 2003), simulation , and theoretical (Botelho et al, 2002;Huber et al, 2004) work suggest that the negative intrinsic curvature of polyunsaturated fatty acid (PUFA)-containing lipids shifts the receptor toward active conformations. Javanainen, et al found in simulations of A2AR that PUFA chains in the first solvation shell mediate partitioning of the receptor into ordered lipid phases, following experimental partitioning measurements in phase separated GUVs reported by Guttierrez and Malmstadt (Javanainen et al, 2019;Gutierrez et al, 2019). Yang and Lyman also reported preferential solvation of A2AR by the monounsaturated chains of dioleyoyl phospholipids relative to saturated lipids (Yang & Lyman, 2019).…”

Section: Introductionmentioning

confidence: 76%

Activation of G-protein-coupled receptors is thermodynamically linked to lipid solvation

Leonard

Lyman

2021

Biophysical Journal

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Preferential lipid solvation of the G-protein coupled A2A adenosine receptor (A2AR) is evaluated from 35 sec of all-atom molecular dynamics simulation. A coarse-grained transition matrix algorithm is developed to overcome slow equilibration of the first solvation shell, obtaining statistically robust estimates of the free energy of solvation by different lipids for the receptor in different activation states. Results indicate preference for solvation by unsaturated chains, which favors the active receptor. A model for lipid-dependent GPCR activity is proposed in which the chemical potential of lipids in the bulk membrane modulates receptor activity. The enthalpy and entropy associated with moving saturated vs. unsaturated lipids from bulk to A2AR's first solvation shell are compared. In the simulated mixture, saturated chains are disordered (i.e., obtain a favorable entropic contribution) when partitioning to the receptor surface, but this is outweighed by a favorable enthalpic contribution for unsaturated chains to occupy the first solvation shell..

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“…The interactions between proteins and lipid membranes in the presence of allosteric modulators are important for understanding of the dynamicity and function of the GPCRs [29][30][31]. Elucidating the mechanism responsible for the protein-lipid interactions or conformational changes in the lipid bilayer may lead to improvements in the field of drug design.…”

Section: Discussionmentioning

confidence: 99%

The Role of Lipids in Allosteric Modulation of Dopamine D2 Receptor—In Silico Study

et al. 2022

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The dopamine D2 receptor, belonging to the class A G protein-coupled receptors (GPCRs), is an important drug target for several diseases, including schizophrenia and Parkinson’s disease. The D2 receptor can be activated by the natural neurotransmitter dopamine or by synthetic ligands, which in both cases leads to the receptor coupling with a G protein. In addition to receptor modulation by orthosteric or allosteric ligands, it has been shown that lipids may affect the behaviour of membrane proteins. We constructed a model of a D2 receptor with a long intracellular loop (ICL3) coupled with Giα1 or Giα2 proteins, embedded in a complex asymmetric membrane, and simulated it in complex with positive, negative or neutral allosteric ligands. In this study, we focused on the influence of ligand binding and G protein coupling on the membrane–receptor interactions. We show that there is a noticeable interplay between the cell membrane, G proteins, D2 receptor and its modulators.

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The lipid phase preference of the adenosine A_2A receptor depends on its ligand binding state

Abstract: As cholesterol fraction increases, ligand-bound receptor occupies more vesicle surface area, demonstrating co-localization with the cholesterol-rich phase.

Cited by 10 publications

References 44 publications

Allosteric modulation of the adenosine A2A receptor by cholesterol

Allosteric modulation of the adenosine A2A receptor by cholesterol

Activation of G-protein-coupled receptors is thermodynamically linked to lipid solvation

The Role of Lipids in Allosteric Modulation of Dopamine D2 Receptor—In Silico Study

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The lipid phase preference of the adenosine A2A receptor depends on its ligand binding state

Abstract: As cholesterol fraction increases, ligand-bound receptor occupies more vesicle surface area, demonstrating co-localization with the cholesterol-rich phase.

Cited by 10 publications

References 44 publications

Allosteric modulation of the adenosine A2A receptor by cholesterol

Allosteric modulation of the adenosine A2A receptor by cholesterol

Activation of G-protein-coupled receptors is thermodynamically linked to lipid solvation

The Role of Lipids in Allosteric Modulation of Dopamine D2 Receptor—In Silico Study

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The lipid phase preference of the adenosine A_2A receptor depends on its ligand binding state