Allosteric modulator desformylflustrabromine relieves the inhibition of alpha2beta2 and alpha4beta2 nicotinic acetylcholine receptors by beta amyloid 1-42 peptide

Monday, October 24, 2011 — Poster Session I
Noon – 2:00 p.m.	Natcher Conference Center	NIEHS	PHARM/PHYS-1

Authors

• A Pandya
• J Yakel

Abstract

Nicotinic acetylcholine receptors (nAChRs) are widely expressed in the brain and they are implicated in the pathophysiology of many neurological conditions, including Alzheimer’s disease (AD). The presence of extracellular neuritic plaques composed of beta amyloid (1-42) peptide is a characteristic feature of AD. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) for alpha4beta2 nAChR subtype. The effect of dFBr on the alpha2beta2 nAChR was unknown. The action of dFBr was tested on alpha2beta2 nAChRs expressed in Xenopus oocytes. It was found that similar to its action on alpha4beta2 receptors, dFBr is also a PAM for the alpha2beta2 receptors. Next we tested whether dFBr had any effect on the previously known block of both the alpha4beta2 and alpha2beta2 receptors by beta amyloid (1-42). We found that the functional blockade of ACh-induced currents in oocytes expressing alpha4beta2 and alpha2beta2 receptors by beta amyloid (1-42) was prevented by dFBr. We conclude that dFBr is a positive allosteric modulator for both alpha4beta2 and alpha2beta2 subtypes of nAChRs, and that it also relieves the blockade of these receptors by beta amyloid (1-42). PAMs for the non-alpha7 nAChRs have the potential to develop into clinically applicable drugs for AD and other disorders.

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