Changes in G protein-mediated signal transduction in aging and Alzheimer's disease.

Abstract

Previous reports have shown that there are age-related reductions in muscarinic receptor (mAChR) sensitivity to agonist stimulation. Our research has elucidated the mechanisms involved in this loss. These studies have shown that this decline is the result of decreases in mAChR concentration, reductions in the number of neuronal cells, and altered phosphoinositide (PI)-mediated signal transduction (ST). The decrements in PI-mediated ST are observed as a reduced ability of muscarinic (m) agonists to enhance K(+)-evoked release of DA (K+ ERDA) from striatal slices from old rats. Additional experiments indicated that the locus of the ST deficits appears to be at the mAChR-G protein interface, since attempts to bypass this interface reduced m-enhanced K+ ERDA deficits in the striata from old rats. Moreover, it appears that the ability of mAChR to decouple from their respective G proteins is reduced as a function of age, since carbachol-stimulated low KM GTPase activity was found to be reduced in hippocampal and striatal tissue obtained from old rats. Similar findings were observed in this parameter in AD hippocampus and basal ganglia. Further reductions were seen in carbachol-stimulated low KM GTPase as a function of the duration of the disease. Results are discussed in terms of structural membrane alterations in aging and disease that may lead to reductions in the efficacy of receptor-G protein coupling/uncoupling.