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. Previous studies have shown that alcohol directly activates GIRK channels through a hydrophobic pocket located in the cytoplasmic domain of the channel. Here, we report the identification and functional characterization of a GIRK1-selective activator, termed GiGA1, that targets the alcohol pocket. GiGA1 activates GIRK1/GIRK2 both in vitro and in vivo and, in turn, mitigates the effects of a convulsant in an acute epilepsy mouse model. These results shed light on the structure-based development of subunit-specific GIRK modulators that could provide potential treatments for brain disorders. Zhao et al. identify GiGA1 through a virtual screen of ∼750,000 chemical compounds using a high-resolution model of the alcohol pocket in GIRK channels. GiGA1 selectively activates GIRK1-containing channels and is G protein independent, like alcohol. GiGA1 activates endogenous GIRK channels in the brain and suppresses induced seizures.
- G-protein-gated inwardly rectifying K channel
- GIRK1-selective activator
- alcohol-like kinetics