Co-expression of Gβ5 enhances the function of two Gγ subunit-like domain-containing regulators of G protein signaling proteins

Regulators of G protein signaling (RGS) stimulate the GTPase activity of G protein Gα subunits and probably play additional roles. Some RGS proteins contain a Gγ subunit-like (GGL) domain, which mediates a specific interaction with Gβ5. The role of such interactions in RGS function is unclear. RGS proteins can accelerate the kinetics of coupling of G protein- coupled receptors to G-protein-gated inwardly rectifying K⁺ (GIRK) channels. Therefore, we coupled m2-muscarinic acetylcholine receptors to GIRK channels in Xenopus oocytes to evaluate the effect of Gβ5 on RGS function. Co- expression of either RGS7 or RGS9 modestly accelerated GIRK channel kinetics. When Gβ5 was co-expressed with either RGS7 or RGS9, the acceleration of GIRK channel kinetics was strongly increased over that produced by RGS7 or RGS9 alone. RGS function was not enhanced by co-expression of Gβ1, and co- expression of Gβ5 alone had no effect on GIRK channel kinetics. Gβ5 did not modulate the function either of RGS4, an RGS protein that lacks a GGL domain, or of a functional RGS7 construct in which the GGL domain was omitted. Enhancement of RGS7 function by Gβ5 was not a consequence of an increase in the amount of plasma membrane or cytosolic RGS7 protein.