The Effect of Membrane Polyunsaturated Fatty Acids on Receptor Partitioning to Ordered Domains

Abstract

Numerous G protein-coupled receptors (GPCRs) contain cholesterol binding sites, and are therefore assumed to partition into cholesterol-rich ordered membrane domains to function properly. Neurotransmitter receptors - many of which are GPCRs and located mainly in the nervous system - are responsible for regulating our behavior and mood, and their compromised signaling often results in neurodegenerative diseases. Interestingly, many such diseases are associated with a decrease in polyunsaturated fatty acid (PUFA) levels in the brain.The PUFAs, usually paired with a saturated lipid tail in hybrid lipids, are known to favorably interact with receptors. This might - in addition to modulating the activation of individual receptors - also affect larger scale GPCR organization, including their partitioning between ordered and disordered membrane domains. However, such effects are very tedious to be studied experimentally, and therefore the determinants of membrane protein partitioning remain currently elusive.Here, using multi-scale computer simulations and free energy calculations, we show that the association of the adenosine A2A receptor, a prototypical GPCR, with the PUFA tail of a hybrid lipid drastically affects its partitioning. The strong PUFA-receptor interaction results in the formation of a well defined lipid corona, whose outer shell is consists of the saturated tails of a hybrid lipid. This cushion softens the membrane perturbation caused by the rough receptor surface and hence makes it more compatible with ordered membrane domains. Interestingly, this favorable solvation by PUFAs seems to be characteristic only for membrane proteins consisting of helical bundles.Our results reveal an unexpected connection between PUFAs and disease: A decrease in the brain PUFA levels might affect GPCR partitioning, thereby compromising their function and perhaps eventually leading to disease. This finding, together with our previous study revealing the role of PUFAs on GPCR oligomerization, highlights the complex interplay of brain membrane lipid composition and neurotransmitter receptor function.