Reduced level of docosahexaenoic acid shifts GPCR neuroreceptors to less ordered membrane regions

PLoS Comput Biol. 2019 May 20;15(5):e1007033. doi: 10.1371/journal.pcbi.1007033. eCollection 2019 May.

Abstract

G protein-coupled receptors (GPCRs) control cellular signaling and responses. Many of these GPCRs are modulated by cholesterol and polyunsaturated fatty acids (PUFAs) which have been shown to co-exist with saturated lipids in ordered membrane domains. However, the lipid compositions of such domains extracted from the brain cortex tissue of individuals suffering from GPCR-associated neurological disorders show drastically lowered levels of PUFAs. Here, using free energy techniques and multiscale simulations of numerous membrane proteins, we show that the presence of the PUFA DHA helps helical multi-pass proteins such as GPCRs partition into ordered membrane domains. The mechanism is based on hybrid lipids, whose PUFA chains coat the rough protein surface, while the saturated chains face the raft environment, thus minimizing perturbations therein. Our findings suggest that the reduction of GPCR partitioning to their native ordered environments due to PUFA depletion might affect the function of these receptors in numerous neurodegenerative diseases, where the membrane PUFA levels in the brain are decreased. We hope that this work inspires experimental studies on the connection between membrane PUFA levels and GPCR signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / metabolism
  • Cholesterol / metabolism
  • Computational Biology
  • Computer Simulation
  • Docosahexaenoic Acids / chemistry
  • Docosahexaenoic Acids / metabolism*
  • Fatty Acids, Unsaturated / metabolism
  • Humans
  • Membrane Microdomains / chemistry
  • Membrane Microdomains / metabolism
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Models, Molecular
  • Models, Neurological
  • Protein Conformation
  • Receptor, Adenosine A2A / chemistry
  • Receptor, Adenosine A2A / metabolism
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism*
  • Sensory Receptor Cells / chemistry
  • Sensory Receptor Cells / metabolism*
  • Signal Transduction
  • Thermodynamics

Substances

  • ADORA2A protein, human
  • Fatty Acids, Unsaturated
  • Membrane Proteins
  • Receptor, Adenosine A2A
  • Receptors, G-Protein-Coupled
  • Docosahexaenoic Acids
  • Cholesterol

Grant support

MJ was funded by the Emil Aaltonen foundation (https://emilaaltonen.fi). IV was funded by an Advanced Grant for the project CROWDED-PRO-LIPIDS by the European Research Council (grant no. 290974, https://erc.europa.eu) and by the Centre of Excellence program of the Academy of Finland (grant no. 307415, http://www.aka.fi). HM-S was funded by the ChemBioDrug project of the European Regional Development Fund OP RDE (grant number CZ.02.1.01/0.0/0.0/16_019/0000729, http://ec.europa.eu/regional_policy/en/funding/erdf). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.