Instability of GGL domain-containing RGS proteins in mice lacking the G protein -subunit G 5

RGS (regulator of G protein signaling) proteins containing the G protein -like (GGL) domain (RGS6, RGS7, RGS9, and RGS11) interact with the fifth member of the G protein -subunit family, G 5. This interaction is necessary for the stability of both the RGS protein and for G 5. Consistent with this notion, we have found that elevation of RGS9-1 mRNA levels by transgene expression does not increase RGS9-1 protein level in the retina, suggesting that G 5 levels may be limiting. To examine further the interactions of G 5 and the GGL domain-containing RGS proteins, we inactivated the G 5 gene. We found that the levels of GGL domain-containing RGS proteins in retinas and in striatum are eliminated or reduced drastically, whereas the levels of G 2 and RGS4 proteins remain normal in the absence of G 5. The homozygous G 5 knockout (G 5 ) mice derived from heterozygous knockout mating are runty and exhibit a high preweaning mortality rate. We concluded that complex formation between GGL domain-containing RGS proteins and the G 5 protein is necessary to maintain their mutual stability in vivo. Furthermore, in the absence of G 5 and all four RGS proteins that form protein complexes with G 5, the animals that survive into adulthood are viable and have no gross defects in brain or retinal morphology.