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J Physiol
2003 Feb 15;547Pt 1:147-57. doi: 10.1113/jphysiol.2002.035436.
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Amyloid beta(1-42) peptide alters the gating of human and mouse alpha-bungarotoxin-sensitive nicotinic receptors.
Grassi F, Palma E, Tonini R, Amici M, Ballivet M, Eusebi F.
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The beta-amyloid(1-42) peptide (Abeta(1-42)), a major constituent of the Alzheimer's disease amyloid plaque, specifically binds to the neuronal alpha-bungarotoxin (alpha-BuTx)-sensitive alpha7 nicotinic acetylcholine receptor (alpha7 nAChR). Accordingly, Abeta1-42 interferes with the function of alpha7 nAChRs in chick and rodent neurons. To gain insights into the human disease, we studied the action of Abeta(1-42) on human alpha7 nAChRs expressed in Xenopus oocytes. In voltage-clamped oocytes expressing the wild-type receptor, Abeta(1-42) blocked ACh-evoked currents. The block was non-competitive, required over 100 s to develop and was partially reversible. In oocytes expressing the mutant L248T receptor, Abeta(1-42) activated methyllycaconitine-sensitive currents in a dose-dependent manner. Peptide-evoked unitary events, recorded in outside-out patches, showed single-channel conductances and open duration comparable to ACh-evoked events. Abeta(1-42) had no effect on the currents evoked by glutamate, GABA or glycine in oocytes expressing human or mouse receptors for these transmitters. Muscle nAChRs are also alpha-BuTx-sensitive and we therefore investigated whether they respond to Abeta(1-42). In human kidney BOSC 23 cells expressing the fetal or adult mouse muscle nAChRs, Abeta(1-42) blocked ACh-evoked whole-cell currents, accelerating their decay. Outside-out single-channel recordings showed that the block was due to a reduced channel open probability and enhanced block upon ACh application. We also report that the inverse peptide Abeta(42-1), but not Abeta(40-1), partially mimicked the effects of the physiological Abeta(1-42) peptide. Possible implications for degenerative neuronal and muscular diseases are discussed.
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