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

• Main Authors: Anna N. Bukiya, Paul S. Blank, Avia Rosenhouse-Dantsker
• Format: Article
• Language: English
• Published: Elsevier 2019-01-01
• Series: Journal of Lipid Research
• Subjects: inwardly rectifying potassium channel; CA1 hippocampal neuron; dietary cholesterol; 3-hydroxy-3-methylglutaryl-CoA reductase; brain lipids; lipid mediators
• Online Access: http://www.sciencedirect.com/science/article/pii/S0022227520326626

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.