Ketamine Reduces the Surface Density of the Astroglial Kir4.1 Channel and Inhibits Voltage-Activated Currents in a Manner Similar to the Action of Ba2+ on K+ Currents.
Mićo Božić, Samo Pirnat, Katja Fink, Maja Potokar, Marko Kreft, Robert Zorec, Matjaž Stenovec
Cells May 10, 2023 DOI: 10.3390/cells12101360 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro laboratory study Peer reviewed |
|---|---|
| Population | Cultured rat and mouse cortical astrocytes |
| Interventions | Ketamine Ba2+ |
| Dose | ketamine 2.5 or 25 µM; dbcAMP 1 mM; extracellular K+ 15 mM; Ba2+ 300 µM |
| Duration | Ketamine treatment 30 min; dbcAMP or elevated K+ treatment 24 h |
| Topics | Ketamine Esketamine |
| Keywords | Kir4.1 Astroglia Camp Membrane current Potassium homeostasis Vesicle mobility |
| Key points | Short-term ketamine treatment reduced Kir4.1-EGFP vesicle mobility in cultured rat astrocytes compared with vehicle controls, an effect mimicked by dbcAMP and elevated extracellular K+, both of which raise intracellular cAMP. In cultured mouse astrocytes, ketamine also reduced Kir4.1 surface density and inhibited voltage-activated currents similar to the Kir4.1 blocker Ba2+. The authors conclude ketamine attenuates Kir4.1 vesicle mobility, likely through a cAMP-dependent mechanism. |
Abstract
A single sub-anesthetic dose of ketamine evokes rapid and long-lasting beneficial effects in patients with a major depressive disorder. However, the mechanisms underlying this effect are unknown. It has been proposed that astrocyte dysregulation of extracellular K+ concentration ([K+]o) alters neuronal excitability, thus contributing to depression. We examined how ketamine affects inwardly rectifying K+ channel Kir4.1, the principal regulator of K+ buffering and neuronal excitability in the brain. Cultured rat cortical astrocytes were transfected with plasmid-encoding fluorescently tagged Kir4.1 (Kir4.1-EGFP) to monitor the mobility of Kir4.1-EGFP vesicles at rest and after ketamine treatment (2.5 or 25 µM). Short-term (30 min) ketamine treatment reduced the mobility of Kir4.1-EGFP vesicles compared with the vehicle-treated controls (p < 0.05). Astrocyte treatment (24 h) with dbcAMP (dibutyryl cyclic adenosine 5'-monophosphate, 1 mM) or [K+]o (15 mM), which increases intracellular cAMP, mimicked the ketamine-evoked reduction of mobility. Live cell immunolabelling and patch-clamp measurements in cultured mouse astrocytes revealed that short-term ketamine treatment reduced the surface density of Kir4.1 and inhibited voltage-activated currents similar to Ba2+ (300 µM), a Kir4.1 blocker. Thus, ketamine attenuates Kir4.1 vesicle mobility, likely via a cAMP-dependent mechanism, reduces Kir4.1 surface density, and inhibits voltage-activated currents similar to Ba2+, known to block Kir4.1 channels.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 3
- Integrating multi-receptor and neuron–glia mechanisms of ketamine's antidepressant action: a convergence framework for understanding efficacy Frontiers in Molecular Neuroscience October 21, 2026
- Astroglia and depression: A Gliocentric perspective from rodent models to therapeutic insights. Progress in Neuro-Psychopharmacology and Biological Psychiatry January 27, 2026
- Unveiling Ketamine's Influence on Astrocytic Kir4.1 Channels Through Multimodal Analysis: Confocal Microscopy, Immunocytochemistry, Fluorescence Analysis, and Electrophysiology. Methods in molecular biology (Clifton, N.J.) 2025
Cites 5
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