scholarly journals Molecular Regulation of α3β4 Nicotinic Acetylcholine Receptors by Lupeol in Cardiovascular System

2020 ◽  
Vol 21 (12) ◽  
pp. 4329
Author(s):  
Sanung Eom ◽  
Chaelin Kim ◽  
Hye Duck Yeom ◽  
Jaeeun Lee ◽  
Shinhui Lee ◽  
...  
Keyword(s):  
Natural Products ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Animal Experiments ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Nicotinic Acetylcholine ◽  
Electrode Voltage ◽  
Treatment Of Hypertension ◽  
Nicotine Acetylcholine Receptor

Cardiovascular disease (CVD) occurs globally and has a high mortality rate. The highest risk factor for developing CVD is high blood pressure. Currently, natural products are emerging for the treatment of hypertension to avoid the side effects of drugs. Among existing natural products, lupeol is known to be effective against hypertension in animal experiments. However, there exists no study regarding the molecular physiological evidence against the effects of lupeol. Consequently, we investigated the interaction of lupeol with α3β4 nicotinic acetylcholine receptors (nAChRs). In this study, we performed a two-electrode voltage-clamp technique to investigate the effect of lupeol on the α3β4 nicotine acetylcholine receptor using the oocytes of Xenopus laevis. Coapplication of acetylcholine and lupeol inhibited the activity of α3β4 nAChRs in a concentration-dependent, voltage-independent, and reversible manner. We also conducted a mutational experiment to investigate the influence of residues of the α3 and β4 subunits on lupeol binding with nAChRs. Double mutants of α3β4 (I37A/N132A), nAChRs significantly attenuated the inhibitory effects of lupeol compared to wild-type α3β4 nAChRs. A characteristic of α3β4 nAChRs is their effect on transmission in the cardiac sympathetic ganglion. Overall, it is hypothesized that lupeol lowers hypertension by mediating its effects on α3β4 nAChRs. The interaction between lupeol and α3β4 nAChRs provides evidence against its effect on hypertension at the molecular-cell level. In conclusion, the inhibitory effect of lupeol is proposed as a novel therapeutic approach involving the antihypertensive targeting of α3β4 nAChRs. Furthermore, it is proposed that the molecular basis of the interaction between lupeol and α3β4 nAChRs would be helpful in cardiac-pharmacology research and therapeutics.

scholarly journals Structural correlates of human muscle nicotinic acetylcholine receptor subunit assembly mediated by δ(+) interface residues

2020 ◽  
Author(s):  
Max Epstein ◽  
Susan Maxwell ◽  
Thomas J. Piggot ◽  
David Beeson ◽  
Isabel Bermudez ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Dynamical Behavior ◽  
Human Muscle ◽  
Amino Acid Residues ◽  
Nicotinic Acetylcholine ◽  
Specific Amino Acid ◽  
Functional Differences ◽  
Electrode Voltage ◽  
Dynamics Simulations

AbstractMuscle nicotinic acetylcholine receptors are a class of heteropentameric ligand-gated cation channels with constituent subunits adopting a fixed stoichiometric arrangement. The specific amino acid residues that govern subunit ordering are however, only partially understood. By integrating all-atom molecular dynamics simulations, bioinformatics, two-electrode voltage clamp electrophysiology and 125I-α-bungarotoxin assays of chimeric nAChR subunits, we identify residues across the extracellular, transmembrane and extended M4 helix of the δ subunit that make structural signatures that contribute to intransigent assembly rules. Furthermore, functional differences observed in α2δ2β receptors can be rationalized by changes in dynamical behavior that manifest themselves at the agonist binding site.

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