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  • Title: Reduced high-affinity agonist binding at the M(1) muscarinic receptor in Alzheimer's disease brain: differential sensitivity to agonists and divalent cations.
    Author: Ladner CJ, Lee JM.
    Journal: Exp Neurol; 1999 Aug; 158(2):451-8. PubMed ID: 10415152.
    Abstract:
    M(1) muscarinic acetylcholine receptor (M(1)AchR)-G protein coupling, as measured by high-affinity agonist binding, was examined in membranes prepared from postmortem human temporal cortex (Brodmann area 38) from individuals with Alzheimer's disease (AD, n = 8) and age-matched controls (n = 6). Binding competitions between the M(1)AchR-selective antagonist [(3)H]pirenzepine ([(3)H]PZ) and muscarinic agonists carbachol, acetylcholine, oxotremorine, and oxotremorine M were conducted. In the presence of 1 mM MgCl(2), the inhibition of [(3)H]PZ binding by carbachol, acetylcholine, or oxotremorine M was best described by a two-affinity state model for control and AD cases, while oxotremorine binding affinity was best fit to a single-state model. Although both control and AD groups had similar K(D) values for the high- and low-affinity agonist binding sites, the proportion of M(1)AchRs exhibiting high affinity for carbachol and acetylcholine was reduced by 48 and 33%, respectively, in AD membranes relative to controls (P < 0.05). No changes in the binding of the oxotremorine M or oxotremorine were noted. The nonhydrolyzable guanine nucleotide GppNHp (100 microM) reduced the proportion of M(1)AchRs with high affinity for agonists in both control and AD membranes. Substitution of 1 mM MnCl(2) for MgCl(2) restored high-affinity carbachol binding at the M(1)AchR in AD membranes similar to that seen in controls. In the presence of 1 mM MnCl(2), agonist binding in controls did not differ from 1 mM MgCl(2). In the absence of cations (1 mM EDTA), no differences between control and AD M(1)AchR carbachol binding were observed. Thus, the loss of high-affinity agonist binding at the M(1)AchR in AD is dependent on the agonist and cation studied.
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