title: Cholesterol up-regulates neuronal G protein-gated inwardly rectifying potassium (GIRK) channel activity in the hippocampus.
abstract: Hypercholesterolemia is a well known risk factor for the development of neurodegenerative disease. However, the underlying mechanisms are mostly unknown. In recent years, it has become increasingly evident that cholesterol-driven effects on physiology and pathophysiology derive from its ability to alter the function of a variety of membrane proteins including ion channels. Yet, the effect of cholesterol on G protein-gated inwardly rectifying potassium (GIRK) channels expressed in the brain is unknown. GIRK channels mediate the actions of inhibitory brain neurotransmitters. As a result, loss of GIRK function can enhance neuron excitability, whereas gain of GIRK function can reduce neuronal activity. Here we show that in rats on a high-cholesterol diet, cholesterol levels in hippocampal neurons are increased. We also demonstrate that cholesterol plays a critical role in modulating neuronal GIRK currents. Specifically, cholesterol enrichment of rat hippocampal neurons resulted in enhanced channel activity. In accordance, elevated currents upon cholesterol enrichment were also observed inXenopusoocytes expressing GIRK2 channels, the primary GIRK subunit expressed in the brain. Furthermore, using planar lipid bilayers, we show that although cholesterol did not affect the unitary conductance of GIRK2, it significantly enhanced the frequency of channel openings. Last, combining computational and functional approaches, we identified two putative cholesterol-binding sites in the transmembrane domain of GIRK2. These findings establish that cholesterol plays a critical role in modulating GIRK activity in the brain. Because up-regulation of GIRK function can reduce neuronal activity, our findings may lead to novel approaches for prevention and therapy of cholesterol-driven neurodegenerative disease.
authors.affiliation: the Department of Pharmacology, The University of Tennessee Health Science Center, Memphis, Tennessee 38103.
authors.forename: Anna N
authors.initials: AN
authors.lastname: Bukiya
authors.affiliation: the Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, T2N 1N4 Canada, and.|the Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul 34353, Turkey.
authors.forename: Serdar
authors.identifier: 0000-0002-0426-0905
authors.initials: S
authors.lastname: Durdagi
authors.affiliation: the Centre for Molecular Simulation and Department of Biological Sciences, University of Calgary, Calgary, AB, T2N 1N4 Canada, and.
authors.forename: Sergei
authors.initials: S
authors.lastname: Noskov
authors.affiliation: From the Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, dantsker@uic.edu.
authors.forename: Avia
authors.initials: A
authors.lastname: Rosenhouse-Dantsker
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015640:Ion Channel Gating / Q000502:physiology*; D008051:Lipid Bilayers / Q000737:chemistry; D008297:Male; D009865:Oocytes; D000072417:Protein Domains; D017966:Pyramidal Cells / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000502:physiology*; D014981:Xenopus
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497069:Kcnj6 protein, mouse; D008051:Lipid Bilayers; D002784:Cholesterol
keywords: G protein-gated inwardly rectifying potassium channel; cholesterol; cholesterol-induced channel activation; electrophysiology; hippocampal CA1 pyramidal neurons; lipid bilayer; lipid-protein interaction; molecular docking; neuron; structure-function