underlying their activity and selectivity. Moreover, future SAR studies and chemical optimization of the existing templates can be performed to improve the specificity of the drugs as well as targeting heterotetramers, such as GIRK1/GIRK3 or GIRK2/GIRK3, for which there are currently no known specific drugs. Additionally, drugs specific for GIRK1/GIRK4 could be developed to treat atrial fibrillation (AF). Thus far, most of the drugs developed are GIRK1/GIRK2 specific. Although these are the most prominent isoforms in the brain, drugs targeting GIRK2/GIRK3 channels in the VTA DA neurons could be useful for treating addiction. Mapping the effects of these drugs on the specific brain circuits will be important for tuning the targeting of these drugs, as well as to develop strategies to achieve not only subunit specificity, but also brain region specificity, in order to avoid undesired side-effects. Similarly, the potential side-effects due to non-cardiac peripheral expression of GIRK channels [56, 57] represent a challenge that should be addressed in the 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
