Activation of G protein-gated K+ channels by G protein-coupled receptors contributes to parasympathetic regulation of heart rate in the atrium and inhibitory postsynaptic potentials in the peripheral and central nervous system. Having found that Gβγ activates the cloned GIRK1 channel, we now report evidence for direct binding of Gβγ to both the N-terminal hydrophilic domain and amino acids 273-462 of the C-terminal domain of GIRK1. These direct interactions are physiologically important because synthetic peptides derived from either domain reduce the Gβγ binding as well as the Gβγ activation of the channel. Moreover, the N-terminal domain may also bind trimeric Gαβγ, raising the possibility that physical association of G protein-coupled receptors, G proteins, and K+ channels partially accounts for their compartmentalization and hence rapid and specific channel activation by receptors.
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