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Changes in G protein-mediated signal transduction in aging and Alzheimer's disease
J A Joseph1, R Cutler, G S Roth
1Gerontology Research Center, NIA/NIH, Baltimore, Maryland 21224.
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.
Insights
Aging reduces muscarinic receptor (mAChR) sensitivity due to lower concentration, fewer neurons, and impaired signal transduction. This impacts dopamine release and receptor-G protein function, potentially due to membrane changes.
Area of Science:
- Neuroscience
- Aging Research
- Pharmacology
Background:
- Age-related decline in muscarinic receptor (mAChR) sensitivity to agonists is documented.
- Mechanisms underlying this sensitivity loss require further elucidation.
Purpose of the Study:
- To investigate the mechanisms behind age-related reductions in mAChR sensitivity.
- To identify the specific molecular deficits in signal transduction pathways.
- To explore the role of receptor-G protein coupling and uncoupling in aging and Alzheimer's disease (AD).
Main Methods:
- Assessed mAChR concentration and neuronal cell counts in aging rat models.
- Measured phosphoinositide (PI)-mediated signal transduction (ST) by evaluating muscarinic agonist-enhanced K(+)-evoked DA release (K+ ERDA) in striatal slices.
- Investigated the mAChR-G protein interface by attempting to bypass it.
- Quantified carbachol-stimulated low KM GTPase activity in hippocampal and striatal tissues from old rats and AD patients.
Main Results:
- Aging is associated with decreased mAChR concentration, reduced neuronal cell numbers, and impaired PI-mediated ST.
- Deficits in PI-mediated ST manifest as reduced muscarinic agonist enhancement of K+ ERDA in aged rats.
- Signal transduction deficits are localized at the mAChR-G protein interface.
- Reduced mAChR-G protein uncoupling, indicated by decreased carbachol-stimulated GTPase activity, is observed in aged and AD brains.
- GTPase activity further diminishes with disease duration in AD.
Conclusions:
- Age-related loss of mAChR sensitivity is attributed to decreased receptor concentration, neuronal loss, and altered PI-mediated ST.
- Impaired mAChR-G protein coupling/uncoupling at the receptor-G protein interface is a key mechanism in aging and AD.
- Structural membrane alterations in aging and disease likely contribute to reduced receptor-G protein interaction efficacy.