Previous investigations had suggested that signaling from the overexpressed beta(2) adrenergic in the heart of transgenic TG4 mice was dampened in the atria. Using an RT-PCR based strategy, we have identified Regulator of G-protein Signaling 5 (RGS5) as being up-regulated in the atria of TG4 mice. Northern blot analysis demonstrated that RGS5 levels were 3 fold higher in the atria of TG4 mice. Western blot analysis of a panel of rat tissues demonstrated that basal expression of RGS5 protein was confined to the heart and skeletal muscle. Furthermore, RGS5 protein was detected in skeletal muscle C2C12 and cardiomyocyte HL-1 cultured cell lines. As observed for RGS5 mRNA levels in TG4 mice, RGS5 protein levels were increased in the atria of rats that were administered the beta adrenergic agonist isoproterenol during a 14 day period. Taken together, these results indicate that RGS5 is a housekeeping RGS in the heart and in skeletal muscle while its beta adrenergic-mediated induction in the atrium suggests that it also has a highly specialized function.