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

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.Author summary: Our current picture of cellular membranes depicts them as laterally heterogeneous sheets of lipids crowded with membrane proteins. These proteins often require a specific lipid environment to efficiently perform their functions. Certain neuroreceptor proteins are regulated by membrane cholesterol that is considered to be enriched in ordered membrane domains. In the brain, these very same domains also contain a fair amount of polyunsaturated fatty acids (PUFAs) that have also been discovered to interact favorably with many receptor proteins. However, certain neurological diseases—associated with the inadequate functioning of the neuroreceptors—seem to result in the decrease of brain PUFA levels. We hypothesized that this decrease in PUFA levels somehow inhibits receptor partitioning to cholesterol-rich domains, which could further compromise their function. We verified our hypothesis by an extensive set of computer simulations. They demonstrated that the PUFA–receptor interaction indeed leads to favorable partitioning of the receptors in the cholesterol-rich ordered domains. Moreover, the underlying mechanism based on the shielding of the rough protein surface by the PUFAs seems to be exclusive for multi-helical protein structures, of which neuroreceptors are a prime example.