Functional and structural interaction of (-)-lobeline with human α4β2 and α4β4 nicotinic acetylcholine receptor subtypes

dc.creatorArias, Hugo Rubén
dc.creatorFeuerbach, Dominik
dc.creatorOrtells, Marcelo Oscar
dc.date2015-07
dc.identifierhttp://hdl.handle.net/11336/38315
dc.identifierArias, Hugo Rubén; Feuerbach, Dominik; Ortells, Marcelo Oscar; Functional and structural interaction of (-)-lobeline with human α4β2 and α4β4 nicotinic acetylcholine receptor subtypes; Pergamon-Elsevier Science Ltd; International Journal Of Biochemistry And Cellular Biology; 64; 7-2015; 15-24
dc.identifier1357-2725
dc.identifierCONICET Digital
dc.identifierCONICET
dc.descriptionTo determine the pharmacologic activity of (-)-lobeline between human (h)α4β2 and hα4β4 nicotinic acetylcholine receptors (AChRs), functional and structural experiments were performed. The Ca2+ influx results established that (-)-lobeline neither actives nor enhances the function of the studied AChR subtypes, but competitively inhibits hα4β4 AChRs with potency ∼10-fold higher than that for hα4β2 AChRs. This difference is due to a higher binding affinity for the [3H]cytisine sites at hα4β4 compared to hα4β2 AChRs, which, in turn, can be explained by our molecular dynamics (MD) results: (1) higher stability of (-)-lobeline and its hydrogen bonds within the α4β4 pocket compared to the α4β2 pocket, (2) (-)-lobeline promotes Loop C to cap the binding site at the α4β4 pocket, but forces Loop C to get apart from the α4β2 pocket, precluding the gating process elicited by agonists, and (3) the orientation of (-)-lobeline within the α4β4, but not the α4β2, subpocket, promoted by the t-(or t+) rotameric state of α4-Tyr98, remains unchanged during the whole MD simulation. This study gives a detailed view of the molecular and dynamics events evoked by (-)-lobeline supporting the differential binding affinity and subsequent inhibitory potency between hα4β2 and hα4β4 AChRs, and supports the possibility that the latter subtype is also involved in its activity.
dc.descriptionFil: Arias, Hugo Rubén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. California Northstate University. College of Medicine. Department of Medical Education; Estados Unidos
dc.descriptionFil: Feuerbach, Dominik. Novartis Institutes for Biomedical Research. Neuroscience Research; Suiza
dc.descriptionFil: Ortells, Marcelo Oscar. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Morón; Argentina
dc.formatapplication/pdf
dc.formatapplication/pdf
dc.languageeng
dc.publisherPergamon-Elsevier Science Ltd
dc.relationinfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.biocel.2015.03.003
dc.relationinfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S1357272515000722
dc.rightsinfo:eu-repo/semantics/openAccess
dc.rightshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject(-)-Lobeline
dc.subjectAcetylcholine Receptors
dc.subjectCa≪Sup≫2+≪/Sup≫Influx
dc.subjectCompetitive Antagonist
dc.subjectHuman Α4 Β2 And Α4 Β4 Nicotinic
dc.subjectMolecular Modeling
dc.subjecthttps://purl.org/becyt/ford/1.6
dc.subjecthttps://purl.org/becyt/ford/1
dc.titleFunctional and structural interaction of (-)-lobeline with human α4β2 and α4β4 nicotinic acetylcholine receptor subtypes
dc.typeinfo:eu-repo/semantics/article
dc.typeinfo:ar-repo/semantics/artículo
dc.typeinfo:eu-repo/semantics/publishedVersion


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