title: Selective ligand behaviors provide new insights into agonist activation of nicotinic acetylcholine receptors.
abstract: Nicotinic acetylcholine receptors are a diverse set of ion channels that are essential to everyday brain function. Contemporary research studies selective activation of individual subtypes of receptors, with the hope of increasing our understanding of behavioral responses and neurodegenerative diseases. Here, we aim to expand current binding models to help explain the specificity seen among three activators of α4β2 receptors: sazetidine-A, cytisine, and NS9283. Through mutational analysis, we can interchange the activation profiles of the stoichiometry-selective compounds sazetidine-A and cytisine. In addition, mutations render NS9283--currently identified as a positive allosteric modulator--into an agonist. These results lead to two conclusions: (1) occupation at each primary face of an α subunit is needed to activate the channel and (2) the complementary face of the adjacent subunit dictates the binding ability of the agonist.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Marotta
authors.forename: Iva
authors.initials: I
authors.lastname: Rreza
authors.forename: Henry A
authors.initials: HA
authors.lastname: Lester
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Dougherty
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D001384:Azetidines / Q000737:chemistry / Q000494:pharmacology*; D001392:Azocines / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018722:Nicotinic Agonists / Q000737:chemistry / Q000494:pharmacology*; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011807:Quinolizines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D001384:Azetidines; D001392:Azocines; D008024:Ligands; D018722:Nicotinic Agonists; D010069:Oxadiazoles; D011725:Pyridines; D011807:Quinolizines; D011978:Receptors, Nicotinic; C561896:3-(3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile; C403531:nicotinic receptor alpha4beta2; C514816:sazetidine-A; C004712:cytisine; D000093843:Quinolizidine Alkaloids