Hydroxy Pentacyclic Triterpene Acid, Kaempferol, Inhibits the Human 5-Hydroxytryptamine Type 3A Receptor Activity

Shinhui Lee,Chaelin Kim,Tae-Hwan Kim,Junho H Lee,Hee-Soo Seol,Jong-Hwan Park,Jaeeun Lee,Sanung Eom

doi:10.3390/ijms23010544

Shinhui Lee, Chaelin Kim + Show 6 more

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https://doi.org/10.3390/ijms23010544

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Abstract

Monoamine serotonin is a major neurotransmitter that acts on a wide range of central nervous system and peripheral nervous system functions and is known to have a role in various processes. Recently, it has been found that 5-HT is involved in cognitive and memory functions through interaction with cholinergic pathways. The natural flavonoid kaempferol (KAE) extracted from Cudrania tricuspidata is a secondary metabolite of the plant. Recently studies have confirmed that KAE possesses a neuroprotective effect because of its strong antioxidant activity. It has been confirmed that KAE is involved in the serotonergic pathway through an in vivo test. However, these results need to be confirmed at the molecular level, because the exact mechanism that is involved in such effects of KAE has not yet been elucidated. Therefore, the objective of this study is to confirm the interaction of KAE with 5-HT3A through electrophysiological studies at the molecular level using KAE extracted from Cudrania tricuspidata. This study confirmed the interaction between 5-HT3A and KAE at the molecular level. KAE inhibited 5-HT3A receptors in a concentration-dependent and voltage-independent manner. Site-directed mutagenesis and molecular-docking studies confirmed that the binding sites D177 and F199 are the major binding sites of human 5-HT3A receptors of KAE.

Highlights

Monoamine serotonin (5-HT, 5-hydroxytryptamine) is a major neurotransmitter that acts on a wide range of central nervous system (CNS) and peripheral nervous system (PNS)
While other 5-HT receptors (5-HTRs) are G-protein coupled receptors (GPCRs) that serve as second messengers [5], 5-HT3 receptors are ligand-gated cation channels activated by binding of ligand for rapid synaptic neurotransmission [6]
To confirm the activity of kaempferol (KAE) for 5-HT3A receptors, serotonin and KAE were applied to oocytes expressing human 5-HT3A

Summary

Introduction

It has been found that 5-HT is involved in cognitive and memory functions through interaction with cholinergic pathways [3]. Receptors that are activated by serotonin are divided into. While other 5-HT receptors (5-HTRs) are G-protein coupled receptors (GPCRs) that serve as second messengers [5], 5-HT3 receptors are ligand-gated cation channels activated by binding of ligand for rapid synaptic neurotransmission [6]. 5-HT3A is a representative receptor of 5-HT3 Rs comprising five A subunits to form a homomeric pentamer with subunits surrounding the central ion-permeable pore [7]. The ligand-binding site of 5-HT3A is a ‘conserved aromatic cage’ formed by W63, Y126, W156, Y207, and F199 at the A+A interaction surface of the extracellular domain (ECD) [8]

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