Advances in Targeting GIRK Channels in Disease

G protein-gated inwardly rectifying potassium (GIRK) channels are essential regulators of cell excitability in the brain. While they are implicated in a variety of neurological diseases in both human and animal model studies, their therapeutic potential has been largely untapped. Here, we review recent advances in the development of small molecule compounds that specifically modulate GIRK channels and compare them with first-generation compounds that exhibit off-target activity. We describe the method of discovery of these small molecule modulators, their chemical features, and their effects in vivo. These studies provide a promising outlook on the future development of subunit-specific GIRK modulators to regulate neuronal excitability in a brain region-specific manner. GIRK channels are important regulators of cellular excitability and have been largely overlooked as potential therapeutic targets for the treatment of neurological diseases.Recent efforts have led to the identification of potent and selective small molecule modulators of GIRK channels.GIRK-specific modulators display promising effects in vivo.Identifying drugs for specific GIRK channel subunits remains a challenge.