Synergistic Roles for G-protein γ3 and γ7 Subtypes in Seizure Susceptibility as Revealed in Double Knock-out Mice

The functions of differentG-protein alpha beta gamma subunit combinations are traditionally ascribed to their various alpha components. However, the discovery of similarly diverse gamma subtypes raises the possibility that they may also contribute to specificity. To test this possibility, we used a gene targeting approach to determine whether the closely related gamma(3) and gamma(7) subunits can perform functionally interchangeable roles in mice. In contrast to single knock-out mice that show normal survival, Gng3(-/-) Gng7(-/-) double knock-out mice display a progressive seizure disorder that dramatically reduces their median life span to only 75 days. Biochemical analyses reveal that the severe phenotype is not due to redundant roles for the two gamma subunits in the same signaling pathway but rather is attributed to their unique actions in different signaling pathways. The results suggest that the gamma(3) subunit is a component of a G(i/o) protein that is required for gamma-aminobutyric acid, type B, receptor-regulated neuronal excitability, whereas the gamma(7) subunit is a component of a G(olf) protein that is responsible for A(2A) adenosine or D-1 dopamine receptor-induced neuro-protective response. The development of this mouse model offers a novel experimental framework for exploring how signaling pathways integrate to produce normal brain function and how their combined dysfunction leads to spontaneous seizures and premature death. The results underscore the critical role of the gamma subunit in this process.