GIRK channels are also activated following stimulation of G protein-coupled receptors (GPCR) such as m2 muscarinic receptors (m2R). The mechanism of G protein activation has been extensively studied. Agonist binding to the GPCR leads to activation of the pertussis toxin sensitive G protein heterotrimer (Gαβγ), allowing the Gβγ subunits to associate directly with the channel and induce channel activation12,13. Mutagenesis and chimeric studies have identified several regions in the cytoplasmic domains of GIRK channels involved in Gβγ binding and activation14-19. Interestingly, pertussis-toxin treatment, which prevents GPCR-mediated G protein activation of GIRK channels, does not prevent alcohol activation8. These experiments suggest that alcohol activation occurs through a mechanism distinct from G protein activation.
