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J Physiol Volume 547, Number 1, 147-157, February 15, 2003 DOI: 10.1113/jphysiol.2002.035436
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J Physiol (2003), 547.1, pp. 147-157
© Copyright 2003 D 2003 The Physiological Society
DOI: 10.1113/jphysiol.2002.035436

Amyloid beta1-42 peptide alters the gating of human and mouse alpha-bungarotoxin-sensitive nicotinic receptors

Francesca Grassi *†‡, Eleonora Palma *†‡, Raffaella Tonini †‡, Mascia Amici †, Marc Ballivet § and Fabrizio Eusebi †‡

† Istituto Pasteur-Fondazione Cenci Bolognetti and Dipartimento di Fisiologia Umana e Farmacologia, Università 'La Sapienza' P.le A. Moro 5, I-00185 Roma, ‡ Dipartimento di Scienze Internistiche, San Raffaele alla Pisana, Tosinvest-Sanita', via della Pisana 235, I00163 Roma, Italy and §Département de Biochimie, Université de Genève, 1211 Genève 4, Switzerland

The beta-amyloid1-42 peptide (Abeta1-42), 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 Abeta1-42 on human alpha7 nAChRs expressed in Xenopus oocytes. In voltage-clamped oocytes expressing the wild-type receptor, Abeta1-42 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, Abeta1-42 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. Abeta1-42 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 Abeta1-42. In human kidney BOSC 23 cells expressing the fetal or adult mouse muscle nAChRs, Abeta1-42 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 Abeta42-1, but not Abeta40-1, partially mimicked the effects of the physiological Abeta1-42 peptide. Possible implications for degenerative neuronal and muscular diseases are discussed.



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