Differences in regional and subcellular localization of G(q/11) and RGS4 protein levels in Alzheimer's disease: correlation with muscarinic M1 receptor binding parameters.

Deficits in M1 muscarinic receptor system signaling in Alzheimer's disease (AD) prompted an analysis of components of these systems, namely, the G(q/11) protein and the regulator of G-protein signaling (RGS) 4 protein. In AD parietal cortex, total levels of G(q/11) and RGS4 proteins were significantly lower than age-matched control cases by 40% and 53%, respectively. However, the levels of membrane-bound G(q/11) and RGS4 protein in AD parietal cortex were maintained at levels comparable to controls. Furthermore, in the frontal cortex and cerebellum both the total and membrane levels of G(q/11) and RGS4 protein were not altered in AD cases compared to control cases. To our knowledge, this is the first report to examine RGS proteins in AD. Using receptor binding assays on the parietal cortex membrane fractions from AD cases, we found the muscarinic agonist carbachol still bound to high- and low-affinity sites (two-site fit) and the potency of 5-guanylylimidodiphosphate (GppNHp) to shift receptors from the high- to low-affinity state (based on the ternary complex model) was greater in AD cases compared to controls. In contrast, we previously reported a lack of high-affinity agonist binding sites in the frontal cortex in AD cases even in the absence of GppNHp. The data suggest that the equilibrium dynamics between the cytosolic and membrane levels of G(q/11) and RGS4 may contribute to the regional differences in the coupling of muscarinic M1 receptors in AD and have implications for the variability in effects of cholingeric treatment strategies currently in place.