Specificity of Gβγ signaling depends on Gα subunit coupling with G-protein-sensitive K channels

Many neurotransmitters activate G-protein-gated inwardly rectifying K ⁺ (Kir3) channels by stimulating G-protein-coupled receptors. However, in native systems, only receptors coupled to pertussis-toxin (PTX)-sensitive G proteins (Gi/Go) have been shown to be able to activate Kir3 channels through the βγ subunits of G proteins (Gβγ), whereas activation of receptors coupled to PTX-insensitive G proteins such as Gq or Gs do not activate Kir3 channels. The question remains as to how signaling specificity is achieved and what are its key determinants. In this study, we have used the Xenopus oocyte expression system to investigate specific activation of Kir3 channels by heterotrimeric G proteins. We have demonstrated the activation of Kir3.4 channels by agonist stimulation of non-PTX-sensitive G proteins under conditions of Gα subunit overexpression. We present evidence to suggest a key role for the coupling efficiency of Gα subunits in determining the specificity of Gβγ signaling to the channel.