future regarding drugs targeting cardiac GIRK1/GIRK4. In parallel with drug development, functional, biochemical, and structural studies should be employed to better understand the site of action and the mechanism by which drug binding alters channel function. For instance, the isoform specificity and whether they are activators or inhibitors has been elucidated for many of these drugs. However, the structural and molecular mechanisms underlying these actions still remain unclear. Currently, all mechanisms are based on site-directed mutagenesis with guidance by computational models in some instances. Biochemical assays, such as chemical crosslinking and mass spectrometry, or solving structures of the current drugs bound to their targets using cryo-electron microscopy (CryoEM) or X-ray crystallography would help improve drug design. These data could then be used in a feedback loop to inform the optimization).
