Abstract
Neuronal nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop superfamily of ligand-gated ion channels. nAChRs are involved in modulating nicotinic-based signal transmission in the central nervous system and are implicated in a range of disorders. Desformylflustrabromine (dFBr) is a positive allosteric modulator that potentiates α4β2 nAChRs. It has been reported that dFBr is selective for the α4β2 receptor relative to other common nAChR subtypes (Neurosci Lett 373:144–149, 2005). Coapplication of dFBr with acetylcholine (ACh) produces a bell-shaped dose–response curve with a peak potentiation of more than 265% (Bioorg Med Chem Lett 17:4855–4860, 2007) at dFBr concentrations <10 μM and inhibition of responses at concentrations >10 μM. The potentiation and inhibition components of dFBr-modulated responses were examined by using two-electrode voltage clamp and human α4β2 nAChRs expressed in Xenopus laevis oocytes. Currents to both partial and full agonists were potentiated by dFBr. Responses to low-efficacy agonists were potentiated significantly more than responses to high-efficacy agonists. Antagonist pIC50 values were unaffected by coapplication of dFBr. In addition to its potentiating effects, dFBr was able to induce current spikes when applied to desensitized receptors, suggestive of a shift in equilibrium from the desensitized to open conformation. In contrast to potentiation, inhibition of ACh responses by dFBr depends on membrane potential and is probably the result of open-channel block by dFBr and ACh. Our data indicate distinct mechanisms for the potentiation and inhibition components of dFBr action. dFBr could prove useful for therapeutic enhancement of responses at α4β2-containing synapses.
Footnotes
This research was supported by the National Center for Research Resources [Grant 5P20RR016466]; the Alaska Institutional Development Award Networks of Biomedical Excellence; and the National Institutes of Health, National Institutes of Neurological Disorders and Stroke [Grant 1R01NS066059].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.167684.
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ABBREVIATIONS:
- nAChR
- neuronal nicotinic acetylcholine receptor
- PAM
- positive allosteric modulator
- dFBr
- desformylflustrabromine
- DHβE
- dihydro-β-erythroidine
- ACh
- acetylcholine
- DMAB
- p-dimethylaminobenzaldehyde
- V/I
- voltage versus current
- PNU-120596
- 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea.
- Received March 2, 2010.
- Accepted May 28, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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