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A role for a specific cholesterol interaction in stabilizing the Apo configuration of the human A(2A) adenosine receptor.

ABSTRACT: The function of G-protein-coupled receptors is tightly modulated by the lipid environment. Long-timescale molecular dynamics simulations (totaling approximately 3 mus) of the A(2A) receptor in cholesterol-free bilayers, with and without the antagonist ZM241385 bound, demonstrate the instability of helix II in the apo receptor in cholesterol-poor membrane regions. We directly observe that the effect of cholesterol binding is to stabilize helix II against a buckling-type deformation, perhaps rationalizing the observation that the A(2A) receptor couples to G protein only in the presence of cholesterol (Zezula and Freissmuth, 2008). The results suggest a mechanism by which the A(2A) receptor may function as a coincidence detector, activating only in the presence of both cholesterol and agonist. We also observed a previously hypothesized conformation of the tryptophan "rotameric switch" on helix VI in which a phenylalanine on helix V positions the tryptophan out of the ligand binding pocket.

SUBMITTER: Lyman E

PROVIDER: S-EPMC2796422 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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A role for a specific cholesterol interaction in stabilizing the Apo configuration of the human A(2A) adenosine receptor.

Lyman Edward E Higgs Chris C Kim Byungchan B Lupyan Dmitry D Shelley John C JC Farid Ramy R Voth Gregory A GA

Structure (London, England : 1993) 20091201 12

The function of G-protein-coupled receptors is tightly modulated by the lipid environment. Long-timescale molecular dynamics simulations (totaling approximately 3 mus) of the A(2A) receptor in cholesterol-free bilayers, with and without the antagonist ZM241385 bound, demonstrate the instability of helix II in the apo receptor in cholesterol-poor membrane regions. We directly observe that the effect of cholesterol binding is to stabilize helix II against a buckling-type deformation, perhaps ratio ...[more]

PMID: 20004169

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Project description:Adenosine is generated in increased concentrations at sites of injury/hypoxia and mediates a variety of physiological and pharmacological effects via G protein-coupled receptors (A(1), A(2A), A(2B), and A(3)). Because all adenosine receptors are expressed on osteoclasts, we determined the role of A(2A) receptor in the regulation of osteoclast differentiation. Differentiation and bone resorption were studied as the macrophage colony-stimulating factor-1-receptor activator of NF-κB ligand formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive cells from primary murine bone marrow-derived precursors. A(2A) receptor and osteoclast marker expression levels were studied by RT-PCR. Cytokine secretion was assayed by enzyme-linked immunosorbent assay. In vivo examination of A(2A) knockout (KO)/control bones was determined by TRAP staining, micro-computed tomography, and electron microscopy. The A(2A) receptor agonist, CGS21680, inhibited osteoclast differentiation and function (half maximal inhibitory concentration, 50 nmol/L), increased the percentage of immature osteoclast precursors, and decreased IL-1β and tumor necrosis factor-α secretion, an effect that was reversed by the A(2A) antagonist, ZM241385. Cathepsin K and osteopontin mRNA expression increased in control and ZM241385-pretreated osteoclasts, and this was blocked by CGS21680. Micro-computed tomography of A(2A)KO mouse femurs showed a significantly decreased bone volume/trabecular bone volume ratio, decreased trabecular number, and increased trabecular space. A(2A)KO femurs showed an increased TRAP-positive osteoclast. Electron microscopy in A(2A)KO femurs showed marked osteoclast membrane folding and increased bone resorption. Thus, adenosine, acting via the A(2A) receptor, inhibits macrophage colony-stimulating factor-1-receptor activator of NF-κB ligand-stimulated osteoclast differentiation and may regulate bone turnover under conditions in which adenosine levels are elevated.

Dataset Information

A role for a specific cholesterol interaction in stabilizing the Apo configuration of the human A(2A) adenosine receptor.

Publications

A role for a specific cholesterol interaction in stabilizing the Apo configuration of the human A(2A) adenosine receptor.

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