Membrane Cholesterol Depletion Reduces Downstream Signaling Activity of the Adenosine A(2a) Receptor
| Autor: | Lewen Yang, Claire McGraw, Edward Lyman, Anne S. Robinson, Ilya Levental |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Receptor Adenosine A2A Cholestyramine Resin Biophysics Adenosine A2A receptor Molecular Dynamics Simulation Biochemistry Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Humans Receptor G protein-coupled receptor chemistry.chemical_classification Chemistry Cholesterol beta-Cyclodextrins Cell Biology Ligand (biochemistry) Cell biology Amino acid 030104 developmental biology Membrane HEK293 Cells Membrane protein lipids (amino acids peptides and proteins) 030217 neurology & neurosurgery Signal Transduction |
| Popis: | Cholesterol has been shown to modulate the activity of multiple G Protein-coupled receptors (GPCRs), yet whether cholesterol acts through specific interactions, indirectly via modifications to the membrane, or via both mechanisms is not well understood. High-resolution crystal structures of GPCRs have identified bound cholesterols; based on a β2-adrenergic receptor (β2AR) structure bound to cholesterol and the presence of conserved amino acids in class A receptors, the cholesterol consensus motif (CCM) was identified. Here in mammalian cells expressing the adenosine A2A receptor (A2AR), ligand dependent production of cAMP is reduced following membrane cholesterol depletion with methyl-beta-cyclodextrin (MβCD), indicating that A2AR signaling is dependent on cholesterol. In contrast, ligand binding is not dependent on cholesterol depletion. All-atom molecular simulations suggest that cholesterol interacts specifically with the CCM when the receptor is in an active state, but not when in an inactive state. Taken together, the data support a model of receptor state-dependent binding between cholesterol and the CCM, which could facilitate both G-protein coupling and downstream signaling of A2AR. |
| Databáze: | OpenAIRE |
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