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Functional and Structural Interaction of (-)-Lobeline with human α4β2 and α4β4 Nicotinic Acetylcholine Receptor Subtypes

Arias, HR, Feuerbach, Dominik and Ortells, Marcelo (2015) Functional and Structural Interaction of (-)-Lobeline with human α4β2 and α4β4 Nicotinic Acetylcholine Receptor Subtypes. Int. J. Biochem. Cell Bio.


To 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 inhibits hα4β4 AChRs with potency (IC50 = 0.25 ± 0.04 μM) ~10-fold higher than that for hα4β2 AChRs (2.58 ± 0.50 μM), in a competitive fashion. The [3H]cytisine competition binding results support the concept that (-)-lobeline is a more potent antagonist at hα4β4 AChRs because it has higher binding affinity (Ki = 1.82 ± 0.07 nM) compared to that for the hα4β2 AChR (4.90 ± 0.30 nM). These differences, in turn, can be explained by our molecular dynamics results: (1) higher stability of (-)-lobeline within the α4β4 pocket compared to that at the α4β2 pocket, (2) higher stability of the hydrogen bonds for (-)-lobeline at the α4β4 dimer that is lacking in the α4β2 dimer, (3) (-)-lobeline promotes Loop C to cap the binding site at the α4β4 dimer, but forces Loop C to get apart from the α4β2 binding site, precluding the gating process elicited by agonists, and (4) the orientation of (-)-lobeline within the α4β4 subpocket, but not in the α4β2 subpocket, promoted by the t- (or t+) rotameric state of α4-Tyr98, remains unchanged during the whole MD simulation, allowing the formation of stable hydrogen bonds and capping of Loop C in the binding site. 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. This work corroborates previous studies and supports the possibility that hα4β4 AChRs are also targets for the pharmacological and clinical activity of (-)-lobeline.

Item Type: Article
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45


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