G protein gated inwardly rectifying K+ (GIRK) channels play important roles in regulation of the excitability of the neuronal and cardiac cells and has been thought to form a complex with Gi/o and Gi/o coupled receptors.

  To investigate the functional significance of the complex formation, we made three chimeric receptors (MC9, MC9A and MC9B, Fig. A) of Gq coupled M1R and Gi/o coupled M2R. In the chimeric receptors, most of the intracellular third loop (i3), which is the critical domain for G protein coupling, is derived from M2R and others are from M1R. The GIRK channel current induced by the activation of the chimeric receptor was electrophysiologically recorded. FRET between YFP fused with the chimeric receptors and CFP tagged at the GIRK channel was also analyzed.

  Amplitudes of the GIRK channel current induced by the activation of the chimeric receptors were well correlated with the FRET efficiency between them (Fig. B). From this study, it was suggested that a complex formation of Gi/o coupled receptor and the GIRK channel is necessary for the efficient channel activation.