Reduced level of docosahexaenoic acid shifts GPCR neuroreceptors to less ordered membrane regions
Javanainen, Matti (Czech Academy of Sciences. Institute of Organic Chemistry and Biochemistry)
Enkavi, Giray (Department of Physics. University of Helsinki)
Guixà González, Ramon (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional)
Kulig, Waldemar (Department of Physics. University of Helsinki)
Martinez-Seara, Hector (Czech Academy of Sciences. Institute of Organic Chemistry and Biochemistry)
Levental, Ilya (Department of Integrated Biology and Pharmacology. McGovern Medical School. University of Texas Health Science Center at Houston)
Vattulainen, Ilpo (MEMPHYS - Center for Biomembrane Physics)

Date:	2019
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.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Brain ; Cholesterol ; Computational Biology ; Computer Simulation ; Docosahexaenoic Acids ; Fatty Acids, Unsaturated ; Humans ; Membrane Microdomains ; Membrane Proteins ; Models, Molecular ; Models, Neurological ; Protein Conformation ; Receptor, Adenosine A2A ; Receptors, G-Protein-Coupled ; Sensory Receptor Cells ; Signal Transduction ; Thermodynamics
Published in:	PLoS computational biology, Vol. 15 Núm. 5 (may 2019) , p. e1007033, ISSN 1553-7358

DOI: 10.1371/journal.pcbi.1007033
PMID: 31107861

16 p, 2.6 MB

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