EVIDENCE THAT DIRECT BINDING OF G(BETA-GAMMA) TO THE GIRK1 G-PROTEIN-GATED INWARDLY RECTIFYING K+ CHANNEL IS IMPORTANT FOR CHANNEL ACTIVATION

Activation of G protein-gated K+ channels by G protein-coupled recepto rs contributes to parasympathetic regulation of heart rate in the atri um and inhibitory postsynaptic potentials in the peripheral and centra l nervous system. Having found that G(beta gamma) activates the cloned GIRK1 channel, we now report evidence for direct binding of G(beta ga mma) to both the N-terminal hydrophilic domain and amino acids 273-462 of the C-terminal domain of GIRK1. These direct interactions are phys iologically important because synthetic peptides derived from either d omain reduce the G(beta gamma) binding as well as the G(beta gamma) ac tivation of the channel. Moreover, the N-terminal domain may also bind trimeric G(alpha beta gamma), raising the possibility that physical a ssociation of G protein-coupled receptors, G proteins, and K+ channels partially accounts for their compartmentalization and hence rapid and specific channel activation by receptors.