As important inhibitory downstream effectors of the G-protein-mediated signaling pathway, GIRK channels are implicated in a number of human diseases, such as epilepsy, cardiac arrhythmias, addiction, and alcohol abuse [15–19]. For instance, GIRK2 KO (knockout) mice are more susceptible to spontaneous and pharmacologically induced seizures [15]. A loss-of-function mutation in GIRK4 (Kir3.4 gene) is associated with long QT syndrome [17]. GIRK3 KO mice show increased ethanol binge-like drinking behavior [19]. These and other studies [3] (review article) point to the therapeutic potential of targeting GIRK channels for treating diseases, and the need for developing potent and specific GIRK modulators. Over the last two decades, several studies have demonstrated modulation of GIRK channels by drugs designed for other targets. The availability of high-resolution atomic structures of GIRK2 channels and related inwardly rectifying K+ channels has helped by facilitating structural mechanisms of action and providing a scaffold for structure-based drug design [10, 20–23]. Recently, a number of small molecules have been developed that specifically modulate GIRK channels, and a majority of them show in vivo effects in mitigating the impact of diseases.
