Molecular Biophysics of Class A G Protein Coupled Receptors-Lipids Interactome at a Glance-Highlights from the A2A Adenosine Receptor

Biomolecules. 2023 Jun 7;13(6):957. doi: 10.3390/biom13060957.

Abstract

G protein-coupled receptors (GPCRs) are embedded in phospholipid membrane bilayers with cholesterol representing 34% of the total lipid content in mammalian plasma membranes. Membrane lipids interact with GPCRs structures and modulate their function and drug-stimulated signaling through conformational selection. It has been shown that anionic phospholipids form strong interactions between positively charged residues in the G protein and the TM5-TM6-TM 7 cytoplasmic interface of class A GPCRs stabilizing the signaling GPCR-G complex. Cholesterol with a high content in plasma membranes can be identified in more specific sites in the transmembrane region of GPCRs, such as the Cholesterol Consensus Motif (CCM) and Cholesterol Recognition Amino Acid Consensus (CRAC) motifs and other receptor dependent and receptor state dependent sites. Experimental biophysical methods, atomistic (AA) MD simulations and coarse-grained (CG) molecular dynamics simulations have been applied to investigate these interactions. We emphasized here the impact of phosphatidyl inositol-4,5-bisphosphate (PtdIns(4,5)P2 or PIP2), a minor phospholipid component and of cholesterol on the function-related conformational equilibria of the human A2A adenosine receptor (A2AR), a representative receptor in class A GPCR. Several GPCRs of class A interacted with PIP2 and cholesterol and in many cases the mechanism of the modulation of their function remains unknown. This review provides a helpful comprehensive overview for biophysics that enter the field of GPCRs-lipid systems.

Keywords: A2A adenosine receptor; GPCR; PIP2; cholesterol; coarse graining; molecular dynamics.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Binding Sites
  • Cholesterol / metabolism
  • Humans
  • Mammals / metabolism
  • Molecular Dynamics Simulation*
  • Phospholipids
  • Receptor, Adenosine A2A* / metabolism
  • Receptors, G-Protein-Coupled* / metabolism
  • Receptors, Purinergic P1

Substances

  • Cholesterol
  • Phospholipids
  • Receptors, G-Protein-Coupled
  • Receptors, Purinergic P1
  • Receptor, Adenosine A2A

Grants and funding

This research work represents part of the PhD thesis of ET and was supported by the Hellenic Foundation for Research and Innovation (HFRI) under the HFRI PhD Fellowship grant; Fellowship Number: 1619; Special Accounts of Research Grants/National and Kapodistrian University of Athens (SARG/NKUA) grant No 16227). We thank also Chiesi Hellas for supporting this research (SARG/NKUA, grant No 10354) and SARG/NKUA (grant No 11775 through Fundació Bosch i Gimpera) for supporting post-doctoral work of ET.