Agonist activation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site

• DOI: 10.1073/pnas.1017975108
• Publication Date: 2011-03-22T05:18:24Z
• Authors: JasKiran K. Gill; Mari Savolainen; Gareth T. Young; Ruud Zwart; Emanuele Sher; Neil S. Millar
• Keywords: Allosteric modulator

Conventional nicotinic acetylcholine receptor (nAChR) agonists, such as acetylcholine, act at an extracellular “orthosteric” binding site located the interface between two adjacent subunits. Here, we present evidence of potent activation α7 nAChRs via allosteric transmembrane site. Previous studies have identified a series nAChR-positive modulators (PAMs) that lack agonist activity but are able to potentiate responses orthosteric acetylcholine. It has been shown, for example, TQS acts conventional nAChR PAM. In contrast, found compound with close chemical similarity (4BP-TQS) is nAChRs. Whereas antagonist metyllycaconitine competitively noncompetitive 4BP-TQS. Mutation amino acid (M253L), in cavity proposed being PAMs, completely blocks by this mutation had no significant effect on Conversely, within known (W148F) profound potency (resulting shift ∼200-fold dose-response curve), little curve Computer docking homology model provides both and 4BP-TQS bind intrasubunit cavity. Taken together, these findings provide can occur