Recently, a GIRK1-specific modulator, named G-protein-independent GIRK activator 1 (GiGA1), was discovered through virtual screening against the alcohol pocket in GIRK2 [46]. Alcohol (ethanol) consumption leads to widespread effects not only in the central nervous system (CNS) but also in peripheral organs, like liver and heart. The simplicity of its structure and the lack of a binding site favored an initial hypothesis that the effects of ethanol are due to an alteration in plasma membrane fluidity. However, ethanol has minimal effects on membrane lipids at clinically relevant concentrations [47]. Ethanol interacts with potassium and calcium channels, as well as receptors for glutamate, γ-amino butyric acid (GABA), dopamine, and opioids [48]. In 1999, two different groups demonstrated that ethanol activates brain and cardiac GIRK channels [11, 12]. These researchers also provided evidence that other short-chain alcohols, such as methanol and propanol activated GIRK channels, but longer chain alcohols (> four-carbons) led to channel inhibition [11, 12], suggesting a finite capacity or size of a physical ethanol binding site [47].
