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Allosteric Modulator Desformylflustrabromine Relieves the Inhibition of α2β2 and α4β2 Nicotinic Acetylcholine Receptors by β-Amyloid1–42 Peptide

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Abstract

Nicotinic acetylcholine receptors (nAChRs) are pentameric transmembrane proteins that belong to the cys-loop ligand-gated ion channel family. These receptors are widely expressed in the brain and implicated in the pathophysiology of many neurological conditions, including Alzheimer’s disease (AD), where typical symptoms include the loss of cognitive function and dementia. The presence of extracellular neuritic plaques composed of β amyloid (Aβ1–42) peptide is a characteristic feature of AD. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) for α4β2 nAChRs since it increases peak ACh responses without inducing a response on its own. Previously, the effect of dFBr on the α2β2 nAChR subtype was not known. The action of dFBr was tested on α2β2 receptors expressed in Xenopus oocytes. It was found that dFBr is also a PAM for the α2β2 receptor. Next we tested whether dFBr had any effect on the previously known block of both the α4β2 and α2β2 receptors by Aβ1–42. We found that the functional blockade of ACh-induced currents in oocytes expressing α4β2 and α2β2 receptors by Aβ1–42 was prevented by dFBr. We conclude that dFBr is a positive allosteric modulator for both α4β2 and α2β2 subtypes of nAChRs and that it also relieves the blockade of these receptors by Aβ1–42. This study demonstrates that PAMs for the non-α7 nAChRs have the potential to develop into clinically applicable drugs for AD and other disorders.

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Acknowledgments

We would like to thank Patricia Lamb for the synthesis of mRNA and other molecular biology work. We extend our appreciation to C. Erxleben and R. Saha for advice in preparing the manuscript. This research was supported by the Intramural Research Program of National Institute of Environmental Health Sciences, NIH.

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  1. Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, MD F2-08, P.O. Box 12233, Research Triangle Park, NC, 27709, USA

    Anshul Pandya & Jerrel L. Yakel

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  1. Anshul Pandya
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  2. Jerrel L. Yakel
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Correspondence to Jerrel L. Yakel.

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Pandya, A., Yakel, J.L. Allosteric Modulator Desformylflustrabromine Relieves the Inhibition of α2β2 and α4β2 Nicotinic Acetylcholine Receptors by β-Amyloid1–42 Peptide. J Mol Neurosci 45, 42–47 (2011). https://doi.org/10.1007/s12031-011-9509-3

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  • DOI: https://doi.org/10.1007/s12031-011-9509-3

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