Agonist-induced activation of G protein-activated inward rectifying K⁺ (GIRK) channels requires binding of G_bg subunits, released from G_i/o. Whereas in the Xenopus oocyte expression system agonist-independent GIRK current (I_GIRK) is also dependent on G_bg¹, this issue thus far has not been addressed in native cells such as atrial myocytes. We analyzed acetylcholine (ACh)-induced and agonist-independent I_GIRK in rat atrial myocytes using the membrane-targeted G_bg-scavengers m-Phosducin (m-P) or Ga_i1 expressed by adenoviral gene transfer. Expression of m-P resulted in a constitutive, irreversible reduction of ACh-induced I_GIRK by ~ 75%. The remaining current was completely inhibited by continuous (60 s) or 5–8 brief (5 s) repetitive exposures to ACh (10 mM). This use-dependent component was completely reversible. G_bg-scavenging by m-P, in contrast, did not affect receptor-independent I_GIRK neither in a constitutive nor in a use-dependent fashion, suggesting this mode of GIRK channel activity to be independent of G_bg. Likewise, overexpression of the physiological bg binding protein Ga_i1, in contrast to heterologous expression systems, did not result in augmentation but decreased ACh-induced I_GIRK and had no effect on agonist-independent current. We conclude that in their native signalling environment, in contrast to expression systems, receptor-independent GIRK channel gating does not require binding of G_bg.

¹Rishal I, Porozov Y,Yakubovich D,Varon D, Dascal N (2005) J. Biol. Chem. 280: 16685–16694.