1. Astrocyte Specific Remodeling of Plasmalemmal Cholesterol Composition by Ketamine Indicates a New Mechanism of Antidepressant Action.
- Author
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Lasič E, Lisjak M, Horvat A, Božić M, Šakanović A, Anderluh G, Verkhratsky A, Vardjan N, Jorgačevski J, Stenovec M, and Zorec R
- Subjects
- Animals, Antidepressive Agents therapeutic use, Astrocytes pathology, Cell Membrane metabolism, Cyclic AMP metabolism, Depressive Disorder, Major drug therapy, Exocytosis drug effects, Female, Ketamine therapeutic use, PC12 Cells, Rats, Rats, Wistar, Antidepressive Agents pharmacology, Astrocytes drug effects, Cholesterol metabolism, Ketamine pharmacology
- Abstract
Ketamine is an antidepressant with rapid therapeutic onset and long-lasting effect, although the underlying mechanism(s) remain unknown. Using FRET-based nanosensors we found that ketamine increases [cAMP]
i in astrocytes. Membrane capacitance recordings, however, reveal fundamentally distinct mechanisms of effects of ketamine and [cAMP]i on vesicular secretion: a rise in [cAMP]i facilitated, whereas ketamine inhibited exocytosis. By directly monitoring cholesterol-rich membrane domains with a fluorescently tagged cholesterol-specific membrane binding domain (D4) of toxin perfringolysin O, we demonstrated that ketamine induced cholesterol redistribution in the plasmalemma in astrocytes, but neither in fibroblasts nor in PC 12 cells. This novel mechanism posits that ketamine affects density and distribution of cholesterol in the astrocytic plasmalemma, consequently modulating a host of processes that may contribute to ketamine's rapid antidepressant action.- Published
- 2019
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