RT Journal Article SR Electronic T1 Activation of α7 nicotinic receptors by orthosteric and allosteric agonists: influence on single-channel kinetics and conductance JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.112.080259 DO 10.1124/mol.112.080259 A1 Magda M Palczynska A1 Marie Jindrichova A1 Alasdair J Gibb A1 Neil Millar YR 2012 UL http://molpharm.aspetjournals.org/content/early/2012/08/08/mol.112.080259.abstract AB Nicotinic acetylcholine receptors (nAChRs) are oligomeric transmembrane proteins in which five subunits co-assemble to form a central ion-channel pore. Conventional agonists, such as acetylcholine (ACh), bind to an orthosteric site, located at subunit interfaces in the extracellular domain. More recently, it has been demonstrated that nAChRs can also be activated by ligands binding to an allosteric transmembrane site. In the case of α7 nAChRs, ACh causes rapid activation and almost complete desensitization. In contrast, allosteric agonists such as 4BP-TQS, activate α7 nAChRs more slowly and cause only low levels of apparent desensitization. In the present study, single-channel patch-clamp recording has been used to investigate differences in the mechanism of activation of α7 nAChRs by ACh and 4BP-TQS. The most striking difference between activation by ACh and 4BP-TQS is in single-channel kinetics. In comparison to activation by ACh, single-channel open times and burst lengths are substantially longer (~160-fold and ~800-fold, respectively), and shut times shorter (~8-fold), when activated by 4BP-TQS. In addition, co-application of ACh and 4BP-TQS results in a further increase in single-channel burst lengths. Mean burst lengths seen when the two agonists are co-applied (3099 ± 754 ms) are ~2.5-fold longer than with 4BP-TQS alone and ~370-fold longer than with ACh alone. Intriguingly, the main single-channel conductance of α7 nAChRs, was significantly larger when activated by 4BP-TQS (100.3 ± 2.4 pS) than when activated by ACh (90.0 ± 2.7 pS), providing evidence that activation by allosteric and orthosteric agonists result in different α7 nAChRs open-channel conformations.