主経路結合アゴニストは,ニコチン受容体におけるチャネルゲートに結合する

Won Yong Lee¹, Steven M Sine

¹Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.

Nature

|November 11, 2005

まとめ

研究者らは,神経伝達物質の結合とシナプス受容体のイオンチャネル開通を結びつける重要な経路を特定した. このアロステリック経路は,特定の残留相互作用を含み,神経生物学における信号伝達を説明します.

科学分野:

神経生物学神経生物学とは
構造生物学構造生物学とは
バイオフィジックス生物物理学

背景:

シナプス受容体は神経伝達に不可欠であり,神経伝達物質の結合をイオンチャネル開通に変換します.
神経伝達物質の結合が離散経路に伝達されるメカニズムは,根本的な問題です.

研究の目的:

神経伝達物質の結合とシナプス受容体のチャネルゲーティングを結びつける主要なアロステル経路の描写.
信号伝導に起因する特定の残留相互作用を解明する.

主な方法:

トルペド・アセチルコリン受容体の4 Å解像度の構造モデルを使用した.
実行されたシングルチャネル電流記録.
残留ペアの間のエネルギーカップリングを決定する.

主要な成果:

結合ドメインベータシートをチャネルにリンクするアルファサブユニット内の不変アルギニンおよびグルタミン酸残基を特定した.
主要なグルタミン酸/バリン残留物とチャネル形成アルファヘリックス残留物 (プロリン/セリン) の間のエネルギー結合が実証されている.
神経伝達物質の結合をチャネルゲーティングに接続する主要なアロステリック経路を確立しました.

結論:

特定された経路は,神経伝達物質によって誘発されるチャネルゲーティングの構造的およびエネルギー的基盤を提供します.
結合信号をチャンネルに伝送するには,特定の残留間結合が不可欠です.
この研究は,シナプス受容体機能とアロステル調節に関する理解を深める.

さらに関連する動画

07:16

Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission

Published on: August 16, 2018

10:48

Probing Nicotinic Acetylcholine Receptor Function in Mouse Brain Slices via Laser Flash Photolysis of Photoactivatable Nicotine

Published on: January 25, 2019

関連する概念動画

01:19

Ligand-gated Ion Channels

Ligand-gated ion channels are transmembrane proteins with a channel for ions to pass through and a binding site for a ligand. The channel opens only when a ligand attaches to the binding site.
Three Subfamilies of Ligand-gated Ion Channels
Ligand-gated ion channels fall into three subfamilies. The 'Cys-loop' includes the nicotinic acetylcholine receptors, γ-aminobutyric acid (GABA), glycine, and 5-hydroxytryptamine receptors. The second one is the 'Pore-loop' channels that include the...

01:21

G-Protein Gated Ion Channels

GPCRs are primarily responsible for our sense of smell, taste, and vision. The binding of a sensory stimulus activates GPCR to stimulate effector proteins, many of which are ion channels in the sensory organs. GPCRs modulate the opening and closing of the target ion channels either directly by binding them, or by releasing second messengers that activate these channels. As ions move across the membrane, the membrane potential is altered, which induces an appropriate response.
Sensory organs,...

01:30

Ligand-Gated Ion Channel Receptor: Gating Mechanism

Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...

01:15

Cholinergic Receptors: Nicotinic

Nicotinic receptors are ligand-gated ion channels that are activated by acetylcholine and nicotine. Upon activation, they cause a rapid increase in the permeability of cells to K+, Na+, and Ca2+, followed by depolarization and excitation. They are in the autonomic ganglia, skeletal neuromuscular junction, CNS, and adrenal medulla.
There are two types of nicotinic receptors: neuromuscular (NM/NM/N1) and neuronal (NN/NN/N2). The two families differ based on their location and selectivity to...

01:18

Indirect-Acting Cholinergic Agonists: Mechanism of Action

Indirect-acting cholinergic agonists work by interacting with an enzyme called acetylcholinesterase (AChE) in the synaptic cleft. They can be reversible or irreversible inhibitors and have different effects on the enzyme.
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex, leading to...