Arias, Hugo R.; Feuerbach, Dominik; Ortells, Marcelo
Functional and structural interaction of (-)-lobeline with human alpha 4 beta 2 and alpha 4 beta 4 nicotinic acetylcholine receptor subtypes
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 64:15-24, JUL 2015

To determine the pharmacologic activity of (-)-lobeline between human (h)alpha 4 beta 2 and h alpha 4 beta 4 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 h alpha 4 beta 4 AChRs with potency similar to 10-fold higher than that for h alpha 4 beta 2 AChRs. This difference is due to a higher binding affinity for the [H-3]cytisine sites at h alpha 4 beta 4 compared to h alpha 4 beta 2 AChRs, which, in turn, can be explained by our molecular dynamics (MD) results: (1) higher stability of (-)-lobeline and its hydrogen bonds within the alpha 4 beta 4 pocket compared to the alpha 4 beta 2 pocket, (2) (-)-lobeline promotes Loop C to cap the binding site at the alpha 4 beta 4 pocket, but forces Loop C to get apart from the alpha 4 beta 2 pocket, precluding the gating process elicited by agonists, and (3) the orientation of (-)-lobeline within the alpha 4 beta 4, but not the alpha 4 beta 2, subpocket, promoted by the t- (or t+) rotameric state of alpha 4-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 h alpha 4 beta 2 and h alpha 4 beta 4 AChRs, and supports the possibility that the latter subtype is also involved in its activity. (C) 2015 Elsevier Ltd. All rights reserved.

DOI:10.1016/j.biocel.2015.03.003

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