Cholesterol intake and statin use regulate neuronal G protein-gated inwardly rectifying potassium channels

• Published in: Journal of lipid research 2019-01, Vol.60 (1), p.19-29
• Main Authors: Bukiya, Anna N., Blank, Paul S., Rosenhouse-Dantsker, Avia
• Format: Article
• Language: English
• Subjects: 3-hydroxy-3-methylglutaryl-CoA reductase; Animals; Atorvastatin - pharmacology; brain lipids; CA1 hippocampal neuron; CA1 Region, Hippocampal - cytology; CA1 Region, Hippocampal - drug effects; CA1 Region, Hippocampal - physiology; Cholesterol, Dietary - pharmacology; dietary cholesterol; Dietary Supplements; Dose-Response Relationship, Drug; Drug Interactions; Electrophysiological Phenomena - drug effects; G Protein-Coupled Inwardly-Rectifying Potassium Channels - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; inwardly rectifying potassium channel; lipid mediators; lipid signaling; Male; Neurons - drug effects; Neurons - metabolism; Rats; Rats, Sprague-Dawley
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M081240

Cholesterol, a critical component of the cellular plasma membrane, is essential for normal neuronal function. Cholesterol content is highest in the brain, where most cholesterol is synthesized de novo; HMG-CoA reductase controls the synthesis rate. Despite strict control, elevated blood cholesterol levels are common and are associated with various neurological disorders. G protein-gated inwardly rectifying potassium (GIRK) channels mediate the actions of inhibitory brain neurotransmitters. Loss of GIRK function enhances neuron excitability; gain of function reduces neuronal activity. However, the effect of dietary cholesterol or HMG-CoA reductase inhibition (i.e., statin therapy) on GIRK function remains unknown. Using a rat model, we compared the effects of a high-cholesterol versus normal diet both with and without atorvastatin, a widely prescribed HMG-CoA reductase inhibitor, on neuronal GIRK currents. The high-cholesterol diet increased hippocampal CA1 region cholesterol levels and correspondingly increased neuronal GIRK currents. Both phenomena were reversed by cholesterol depletion in vitro. Atorvastatin countered the high-cholesterol diet effects on neuronal cholesterol content and GIRK currents; these effects were reversed by cholesterol enrichment in vitro. Our findings suggest that high-cholesterol diet and atorvastatin therapy affect ion channel function in the brain by modulating neuronal cholesterol levels.