Synergistic roles for G-protein γ3 and γ7 subtypes in seizure susceptibility as revealed in double knock-out mice.
The functions of different G-protein αβγ subunit combinations are traditionally ascribed to their various α components. However, the discovery of similarly diverse γ 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 γ(3) and γ(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 γ subunits in the same signaling pathway but rather is attributed to their unique actions in different signaling pathways. The results suggest that the γ(3) subunit is a component of a G(i/o) protein that is required for γ-aminobutyric acid, type B, receptor-regulated neuronal excitability, whereas the γ(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 γ subunit in this process.
Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania 17822, USA.
William F
WF
Schwindinger
Uyenlinh L
UL
Mirshahi
Kelly A
KA
Baylor
Kathleen M
KM
Sheridan
Anna M
AM
Stauffer
Stephanie
S
Usefof
Mark M
MM
Stecker
Tooraj
T
Mirshahi
Janet D
JD
Robishaw
D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D004827:Epilepsy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D051379:Mice; D018345:Mice, Knockout; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism; D011954:Receptors, Dopamine / Q000235:genetics / Q000378:metabolism; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D044388:GTP-Binding Protein gamma Subunits; C115784:Gng3 protein, mouse; D043705:Receptor, Adenosine A2A; D011954:Receptors, Dopamine; D018080:Receptors, GABA-B; D019206:GTP-Binding Protein alpha Subunits, Gi-Go