The role of members of the pertussis toxin-sensitive family of G proteins in coupling receptors to the activation of the G protein-gated inwardly rectifying potassium channel

Inwardly rectifying potassium (K+) channels gated by G proteins (Kir3.x fam ily) are widely distributed in neuronal, atrial, and endocrine tissues and play key roles in generating late inhibitory postsynaptic potentials, slowi ng the heart rate and modulating hormone release. They are directly activat ed by G(beta gamma) subunits released from G protein heterotrimers of the G (i/o) family upon appropriate receptor stimulation. Here we examine the rol e of isoforms of pertussis toxin (PTx)-sensitive G protein alpha subunits ( G(i alpha 1-3) and G(o alpha A)) in mediating coupling between Various rece ptor systems (A(1), alpha(2A) D-2S M-4, GABA(B)1a+2, and GABA(B)1b+2) and t he cloned counterpart of the neuronal channel (Kir3.1+3.2A). The expression of mutant PTx-resistant G(i/o alpha) subunits in PTx-treated HEK293 cells stably expressing Kir3.1+3.2A allows us to selectively investigate that cou pling. We find that, for those receptors (A(1), alpha(2A)) known to interac t with all isoforms, G(i alpha 1-3) and G(o alpha A) can all support a sign ificant degree of coupling to Kir3.1+3.2A. The Mg receptor appears to prefe rentially couple to G(i alpha 2) while another group of receptors (D-2S, GA BA(B)1a+2, GABA(B)1b+2) activates the channel predominantly through Cp, lib erated from G(oA) heterotrimers. Interestingly, we have also found a distin ct difference in C protein coupling between the two splice variants of GABA (B)1. Our data reveal selective pathways of receptor activation through dif ferent G(i/o alpha) isoforms for stimulation of the G protein-gated inwardl y rectifying K+ channel.