A remarkable aspect of ethanol's effect on brain function is that this simple chemical compound of only two carbons and a hydroxyl produces long-term behavioral changes in humans. Moreover, ethanol has unusually low potency (mM) and weak selectivity (more than one type of alcohol can achieve similar modulation) for ion channel targets. Recently, Bodhinathan and Slesinger (2013) examined the chemical requirements for activation of GIRK channels using an alcohol-tagging strategy originally described for LGIC channels (Mascia et al., 2000). With a cysteine engineered in the alcohol pocket of GIRK2 (L257C in βD-βE loop), tagging the pocket with both alcohol (hydroxyethyl) and non-alcohol (ethyl or benzyl) like chemical groups led to constitutive channel activation. Thus, the hydroxyl per se was not required for chemical activation of GIRK channels, in contrast to modulation with native alcohols. The hydroxyl may be required for stabilizing native alcohols in the pocket through hydrogen bonding. Tagging GIRK2 channels with a hydroxy-benzyl moiety, however, did not activate the channel, indicating that a small increase in side-chain volume was incompatible with channel activation. Importantly, simply attaching alcohol-like compounds
