RT Journal Article
SR Electronic
T1 Positive Allosteric Modulation of the α7 Nicotinic Acetylcholine Receptor: Ligand Interactions with Distinct Binding Sites and Evidence for a Prominent Role of the M2-M3 Segment
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1407
OP 1416
DO 10.1124/mol.107.042820
VO 74
IS 5
A1 Bertrand, Daniel
A1 Bertrand, Sonia
A1 Cassar, Steven
A1 Gubbins, Earl
A1 Li, Jinhe
A1 Gopalakrishnan, M.
YR 2008
UL http://molpharm.aspetjournals.org/content/74/5/1407.abstract
AB The α7 nicotinic acetylcholine receptor (nAChR), a homopentameric, rapidly activating and desensitizing ligand-gated ion channel with relatively high degree of calcium permeability, is expressed in the mammalian central nervous system, including regions associated with cognitive processing. Selective agonists targeting the α7 nAChR have shown efficacy in animal models of cognitive dysfunction. Use of positive allosteric modulators selective for the α7 receptor is another strategy that is envisaged in the design of active compounds aiming at improving attention and cognitive dysfunction. The recent discovery of novel positive allosteric modulators such as 1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethylphenyl)urea (NS-1738) and 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea (PNU-120596) that are selective for the α7 nAChRs but display significant phenotypic differences in their profile of allosteric modulation, suggests that these molecules may act at different sites on the receptor. Taking advantage of the possibility to obtain functional receptors by the fusion of proteins domains from the α7 and the 5-HT3 receptor, we examined the structural determinants required for positive allosteric modulation. This strategy revealed that the extracellular N-terminal domain of α7 plays a critical role in allosteric modulation by NS-1738. In addition, α7-5HT3 chimeras harboring the M2-M3 segment showed that spontaneous activity in response to NS-1738, which confirmed the critical contribution of this small extracellular segment in the receptor gating. In contrast to NS-1738, positive allosteric modulation by PNU-120596 could not be restored in the α7-5HT3 chimeras but was selectively observed in the reverse 5HT3-α7 chimera. All together, these data illustrate the existence of distinct allosteric binding sites with specificity of different profiles of allosteric modulators and open new possibilities to investigate the α7 receptor function. The American Society for Pharmacology and Experimental Therapeutics