title: Sazetidine-A Activates and Desensitizes Native α7 Nicotinic Acetylcholine Receptors.
abstract: The aim of this study was to investigate the ability of sazetidine-A, a novel partial agonist at α4β2 nicotinic acetylcholine receptors (nAChRs), to affect the function of native α7 nAChRs in SH-SY5Y cells and primary cortical cultures. The α7-selective positive allosteric modulator PNU-120596 was used to reveal receptor activation, measured as an increase in intracellular calcium using fluorescent indicators. In the absence of PNU-120596, sazetidine-A elicited mecamylamine-sensitive increases in fluorescence in SH-SY5Y cells (EC50 4.2 µM) but no responses from primary cortical neurons. In the presence on PNU-120596, an additional response to sazetidine-A was observed in SH-SY5Y cells (EC50 0.4 µM) and robust responses were recorded in 14 % of cortical neurons. These PNU-120596-dependent responses were blocked by methyllycaconitine, consistent with the activation of α7 nAChRs. Preincubtion with sazetidine-A concentration-dependently attenuated subsequent responses to the α7-selective agonist PNU-282987 in SH-SY5Y cells (IC50 476 nM) and cortical cultures. These findings support the ability of sazetidine-A to interact with α7 nAChRs, which may contribute to sazetidine-A's actions in complex physiological systems.
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Brown
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK. s.wonnacott@bath.ac.uk.
authors.forename: Susan
authors.initials: S
authors.lastname: Wonnacott
mesh_terms: D000818:Animals; D001384:Azetidines / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D010671:Phenylurea Compounds / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000187:drug effects* / Q000378:metabolism
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; D001384:Azetidines; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D007555:Isoxazoles; C498513:PNU-282987; D010671:Phenylurea Compounds; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; C514816:sazetidine-A; D002118:Calcium
keywords: Live cell calcium imaging; PNU-120596; Primary cortical neurons; SH-SY5Y cells
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