title: A Novel α2/α4 Subtype-selective Positive Allosteric Modulator of Nicotinic Acetylcholine Receptors Acting from the C-tail of an α Subunit.
abstract: Positive allosteric modulators (PAMs) of nicotinic acetylcholine receptors (nAChR) are important therapeutic candidates as well as valuable research tools. We identified a novel type II PAM, (R)-7-bromo-N-(piperidin-3-yl)benzo[b]thiophene-2-carboxamide (Br-PBTC), which both increases activation and reactivates desensitized nAChRs. This compound increases acetylcholine-evoked responses of α2* and α4* nAChRs but is without effect on α3* or α6* nAChRs (* indicates the presence of other nAChR subunits). Br-BPTC acts from the C-terminal extracellular sequences of α4 subunits, which is also a PAM site for steroid hormone estrogens such as 17β-estradiol. Br-PBTC is much more potent than estrogens. Like 17β-estradiol, the non-steroid Br-PBTC only requires one α4 subunit to potentiate nAChR function, and its potentiation is stronger with more α4 subunits. This feature enables Br-BPTC to potentiate activation of (α4β2)(α6β2)β3 but not (α6β2)2β3 nAChRs. Therefore, this compound is potentially useful in vivo for determining functions of different α6* nAChR subtypes. Besides activation, Br-BPTC affects desensitization of nAChRs induced by sustained exposure to agonists. After minutes of exposure to agonists, Br-PBTC reactivated short term desensitized nAChRs that have at least two α4 subunits but not those with only one. Three α4 subunits were required for Br-BPTC to reactivate long term desensitized nAChRs. These data suggest that higher PAM occupancy promotes channel opening more efficiently and overcomes short and long term desensitization. This C-terminal extracellular domain could be a target for developing subtype or state-selective drugs for nAChRs.
authors.affiliation: From the Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kuryatov
authors.affiliation: Department of Molecular Therapeutics, Scripps Research Institute, Scripps, Florida 33458, and.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Jin
authors.affiliation: From the Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Jack
authors.initials: J
authors.lastname: Norleans
authors.affiliation: Department of Molecular Therapeutics, Scripps Research Institute, Scripps, Florida 33458, and.
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kenny
authors.affiliation: From the Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, JSLKK@mail.med.upenn.edu.
authors.forename: Jon
authors.initials: J
authors.lastname: Lindstrom
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D004958:Estradiol
keywords: drug development; electrophysiology; nicotine addition; nicotinic acetylcholine receptors (nAChR); positive allosteric modulator; receptor desensitization; receptor structure-function