Molecular Regulation of Betulinic Acid on α3β4 Nicotinic Acetylcholine Receptors
Betulinic acid (BA) is a major constituent of Zizyphus seeds that have been long used as therapeutic agents for sleep-related issues in Asia. BA is a pentacyclic triterpenoid. It also possesses various anti-cancer and anti-inflammatory effects. Current commercially available sleep aids typically use...
Main Authors: | , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2021-05-01
|
Series: | Molecules |
Subjects: | |
Online Access: | https://www.mdpi.com/1420-3049/26/9/2659 |
id |
doaj-2c5dd943df5143809ab623e8be409b98 |
---|---|
record_format |
Article |
spelling |
doaj-2c5dd943df5143809ab623e8be409b982021-05-31T23:01:53ZengMDPI AGMolecules1420-30492021-05-01262659265910.3390/molecules26092659Molecular Regulation of Betulinic Acid on α3β4 Nicotinic Acetylcholine ReceptorsShinhui Lee0Woog Jung1Sanung Eom2Hye Duck Yeom3Heui-Dong Park4Junho H. Lee5Department of Biotechnology, Chonnam National University, Gwangju 61186, KoreaSchool of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, KoreaDepartment of Biotechnology, Chonnam National University, Gwangju 61186, KoreaGoPath Laboratories, Buffalo Grove, IL 60089, USASchool of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, KoreaDepartment of Biotechnology, Chonnam National University, Gwangju 61186, KoreaBetulinic acid (BA) is a major constituent of Zizyphus seeds that have been long used as therapeutic agents for sleep-related issues in Asia. BA is a pentacyclic triterpenoid. It also possesses various anti-cancer and anti-inflammatory effects. Current commercially available sleep aids typically use GABAergic regulation, for which many studies are being actively conducted. However, few studies have focused on acetylcholine receptors that regulate wakefulness. In this study, we utilized BA as an antagonist of α3β4 nicotinic acetylcholine receptors (α3β4 nAChRs) known to regulate rapid-eye-movement (REM) sleep and wakefulness. Effects of BA on α3β4 nAChRs were concentration-dependent, reversible, voltage-independent, and non-competitive. Site-directed mutagenesis and molecular-docking studies confirmed the binding of BA at the molecular level and showed that the α3 subunit L257 and the β4 subunit I263 residues affected BA binding. These data demonstrate that BA can bind to a binding site different from the site for the receptor’s ligand, acetylcholine (ACh). This suggests that BA may be an effective antagonist that is unaffected by large amounts of ACh released during wakefulness and REM sleep. Based on the above experimental results, BA is likely to be a therapeutically useful sleep aid and sedative.https://www.mdpi.com/1420-3049/26/9/2659α3β4 nAChRbetulinic acidinsomniasleep regulationTEVCZizyphus seed |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shinhui Lee Woog Jung Sanung Eom Hye Duck Yeom Heui-Dong Park Junho H. Lee |
spellingShingle |
Shinhui Lee Woog Jung Sanung Eom Hye Duck Yeom Heui-Dong Park Junho H. Lee Molecular Regulation of Betulinic Acid on α3β4 Nicotinic Acetylcholine Receptors Molecules α3β4 nAChR betulinic acid insomnia sleep regulation TEVC Zizyphus seed |
author_facet |
Shinhui Lee Woog Jung Sanung Eom Hye Duck Yeom Heui-Dong Park Junho H. Lee |
author_sort |
Shinhui Lee |
title |
Molecular Regulation of Betulinic Acid on α3β4 Nicotinic Acetylcholine Receptors |
title_short |
Molecular Regulation of Betulinic Acid on α3β4 Nicotinic Acetylcholine Receptors |
title_full |
Molecular Regulation of Betulinic Acid on α3β4 Nicotinic Acetylcholine Receptors |
title_fullStr |
Molecular Regulation of Betulinic Acid on α3β4 Nicotinic Acetylcholine Receptors |
title_full_unstemmed |
Molecular Regulation of Betulinic Acid on α3β4 Nicotinic Acetylcholine Receptors |
title_sort |
molecular regulation of betulinic acid on α3β4 nicotinic acetylcholine receptors |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2021-05-01 |
description |
Betulinic acid (BA) is a major constituent of Zizyphus seeds that have been long used as therapeutic agents for sleep-related issues in Asia. BA is a pentacyclic triterpenoid. It also possesses various anti-cancer and anti-inflammatory effects. Current commercially available sleep aids typically use GABAergic regulation, for which many studies are being actively conducted. However, few studies have focused on acetylcholine receptors that regulate wakefulness. In this study, we utilized BA as an antagonist of α3β4 nicotinic acetylcholine receptors (α3β4 nAChRs) known to regulate rapid-eye-movement (REM) sleep and wakefulness. Effects of BA on α3β4 nAChRs were concentration-dependent, reversible, voltage-independent, and non-competitive. Site-directed mutagenesis and molecular-docking studies confirmed the binding of BA at the molecular level and showed that the α3 subunit L257 and the β4 subunit I263 residues affected BA binding. These data demonstrate that BA can bind to a binding site different from the site for the receptor’s ligand, acetylcholine (ACh). This suggests that BA may be an effective antagonist that is unaffected by large amounts of ACh released during wakefulness and REM sleep. Based on the above experimental results, BA is likely to be a therapeutically useful sleep aid and sedative. |
topic |
α3β4 nAChR betulinic acid insomnia sleep regulation TEVC Zizyphus seed |
url |
https://www.mdpi.com/1420-3049/26/9/2659 |
work_keys_str_mv |
AT shinhuilee molecularregulationofbetulinicacidona3b4nicotinicacetylcholinereceptors AT woogjung molecularregulationofbetulinicacidona3b4nicotinicacetylcholinereceptors AT sanungeom molecularregulationofbetulinicacidona3b4nicotinicacetylcholinereceptors AT hyeduckyeom molecularregulationofbetulinicacidona3b4nicotinicacetylcholinereceptors AT heuidongpark molecularregulationofbetulinicacidona3b4nicotinicacetylcholinereceptors AT junhohlee molecularregulationofbetulinicacidona3b4nicotinicacetylcholinereceptors |
_version_ |
1721418478292828160 |