Potassium channels play an important role in controlling the electrical activity of neurons in the brain. G-protein-gated inwardly rectifying K+ (GIRK) channels are essential effectors of inhibitory neurotransmission in the brain. GIRK channels have been implicated in diseases with abnormal neuronal excitability, including epilepsy and addiction.
GIRK channels are tetramers composed of either the same subunit (e.g., homotetramers) or different subunits (e.g., heterotetramers). Compounds that specifically target subsets of GIRK channels in vivo are lacking.The authors identified and characterized a new compound, called GiGA1, that selectively opens GIRK potassium channels and can functionally suppress seizures in an epilepsy animal model.
GiGA1 was identified in a library of ~750 thousand chemical compounds, using computer-based modeling and virtual screening of an alcohol-binding pocket in the channel. GiGA1 preferentially activates a subset of GIRK channels, those containing the GIRK1 and GIRK2 subunits, most commonly found in the brain. GiGA1 also activates natively expressed GIRK channels in hippocampal neurons and in turn reduces neuronal excitability. Systemic administration of GiGA1 exhibits anti-seizure properties in an acute epilepsy animal model.
Single-cell electrophysiology demonstrated that GiGA1 has similar properties as alcohol, but is more potent, and activates natively expressed GIRK channels in the hippocampus. Systemic administration of GiGA1 prior to inducing convulsions with pentylenetetrazole (PTZ) significantly reduces the number and severity of seizures.
An anti-seizure molecule that activates brain potassium channel discovered
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