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Dynamic Role of the G Protein in Stabilizing the Active State of the Adenosine A2A Receptor.

ABSTRACT: Agonist binding in the extracellular region of the G protein-coupled adenosine A2A receptor increases its affinity to the G proteins in the intracellular region, and vice versa. The structural basis for this effect is not evident from the crystal structures of A2AR in various conformational states since it stems from the receptor dynamics. Using atomistic molecular dynamics simulations on four different conformational states of the adenosine A2A receptor, we observed that the agonists show decreased ligand mobility, lower entropy of the extracellular loops in the active-intermediate state compared with the inactive state. In contrast, the entropy of the intracellular region increases to prime the receptor for coupling the G protein. Coupling of the G protein to A2AR shrinks the agonist binding site, making tighter receptor agonist contacts with an increase in the strength of allosteric communication compared with the active-intermediate state. These insights provide a strong basis for structure-based ligand design studies.

SUBMITTER: Lee S

PROVIDER: S-EPMC6531377 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Dynamic Role of the G Protein in Stabilizing the Active State of the Adenosine A2A Receptor.

Lee Sangbae S Nivedha Anita K AK Tate Christopher G CG Vaidehi Nagarajan N

Structure (London, England : 1993) 20190131 4

Agonist binding in the extracellular region of the G protein-coupled adenosine A2A receptor increases its affinity to the G proteins in the intracellular region, and vice versa. The structural basis for this effect is not evident from the crystal structures of A2AR in various conformational states since it stems from the receptor dynamics. Using atomistic molecular dynamics simulations on four different conformational states of the adenosine A2A receptor, we observed that t ...[more]

PMID: 30713025

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Project description:ObjectivePharmacological activation of adenosine signaling has been shown to increase ?-cell proliferation and thereby ?-cell regeneration in zebrafish and rodent models of diabetes. However, whether adenosine has an endogenous role in regulating ?-cell proliferation is unknown. The objective of this study was to determine whether endogenous adenosine regulates ?-cell proliferation-either in the basal state or states of increased demand for insulin-and to delineate the mechanisms involved.MethodsWe analyzed the effect of pharmacological adenosine agonists on ?-cell proliferation in in vitro cultures of mouse islets and in zebrafish models with ?- or ?-cell ablation. In addition, we performed physiological and histological characterization of wild-type mice and mutant mice with pancreas- or ?-cell-specific deficiency in Adora2a (the gene encoding adenosine receptor A2a). The mutant mice were used for in vivo studies on the role of adenosine in the basal state and during pregnancy (a state of increased demand for insulin), as well as for in vitro studies of cultured islets.ResultsPharmacological adenosine signaling in zebrafish had a stronger effect on ?-cell proliferation during ?-cell regeneration than in the basal state, an effect that was independent of the apoptotic microenvironment of the regeneration model. In mice, deficiency in Adora2a impaired glucose control and diminished compensatory ?-cell proliferation during pregnancy but did not have any overt phenotype in the basal state. Islets isolated from Adora2a-deficient mice had a reduced baseline level of ?-cell proliferation in vitro, consistent with our finding that UK432097, an A2a-specific agonist, promotes the proliferation of mouse ?-cells in vitro.ConclusionsThis is the first study linking endogenously produced adenosine to ?-cell proliferation. Moreover, we show that adenosine signaling via the A2a receptor has an important role in compensatory ?-cell proliferation, a feature that could be harnessed pharmacologically for ?-cell expansion and future therapeutic development for diabetes.

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Dynamic Role of the G Protein in Stabilizing the Active State of the Adenosine A2A Receptor.

Publications

Dynamic Role of the G Protein in Stabilizing the Active State of the Adenosine A<sub>2A</sub> Receptor.

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