RGS (regulator of G protein signalling) domain-containing proteins are GTPase accelerating proteins specific for Gasubunits. In cardiac atrial myocytes expression of at least seven different RGS proteins including RGS10 has been demonstrated. We measured deactivation of endogenous GIRK current, a target of G_i/o derived Gbg, in atrial myocytes, to study effects of RGS10 on signalling via muscarinic M₂ receptors. Activation of PKA by b-adrenergic stimulation, forskoline, or cAMP-loading via the recording pipette caused a 2-fold increase in deactivation time constant ([tau]d), in line with a previous study on a heterologous expression system demonstrating phosphorylation-dependent translocation of RGS10 to the nucleus.Overexpression of RGS10 by adenoviral gene transfer caused a decrease in [tau]d by 60% that was still sensitive to PKA. Expression of a phosphorylation-deficient mutant (RGS10-S168A) caused a comparable decrease in td that was insensitive to PKA activation. Overexpression of RGS4 (also endogenously expressed in atrial myocytes) resulted in a decrease in [tau]d, comparable to RGS10 overexpression. In those myocytes stimulation of the cAMP pathway did not affect GIRK deactivation, suggesting some exchangeability of RGS proteins in putative GPCR/GIRK/RGSX signalling complexes. Qualitatively comparable results were obtained, when endogenous or overexpressed A₁ receptors were used for activating GIRK channels.