与神经发育障碍相关的GRIN1变异揭示了通道关病理机制
Lotten Ragnarsson1, Zihan Zhang1, Sooraj S Das2
1Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
Epilepsia
|September 21, 2023
概括
GRIN1基因中的遗传变异影响N-甲基-D-酸盐 (NMDA) 受体功能,可能导致神经系统疾病. 该GluN1 (Y668H) 变体显著改变受体功能,突出了神经疾病的关键部位.
科学领域:
- 神经科学是一个神经科学.
- 分子生物学分子生物学
- 遗传学 遗传学 是一个
背景情况:
- N-甲基-D-酸盐 (NMDA) 受体对大脑发育和认知功能至关重要.
- 编码GluN1亚单元的GRIN1基因的突变与严重的神经疾病有关.
- 研究特定GRIN1误解变异的功能影响对于了解疾病机制至关重要.
研究的目的:
- 为了确定GRIN1基因中的三个错误变异的致病性:p.Ile148Val (GluN1-3b[I481V]),p.Ala666Ser (GluN1-3b[A666S]),和p.Tyr668His (GluN1-3b[Y668H]). 为了确定GRIN1基因中的三个错误变异的致病性:p.Ile148Val (GluN1-3b[I481V]),p.Ala666Ser (GluN1-3b[A666S]),和p.Tyr668His (GluN1-3b[Y668H]).
- 描述这些变异对NMDA受体特性的功能后果.
主要方法:
- 野生型和变种NMDA受体在HEK293细胞和原发海马神经元中的表达.
- 补丁电生理学和药理学,以评估受体功能.
- 光标记和显微镜用于评估受体表面表达.
主要成果:
- 这种GluN1 (I481V) 变种显示胺和记忆素的抑制减少.
- GluN1 (A666S) 和GluN1 (Y668H) 变种表现出功能获取的表型,具有改变的甘氨酸敏感性和对道阻断剂的降低/增加敏感性.
- 该GluN1 (Y668H) 变体表现出表面表达受损,对谷氨酸和甘氨酸过敏,以及改变的通道阻塞,具有独特的单通道导电性质.
结论:
- 该研究确定GluN1(Y668) 作为一个关键的功能位点合受体,对离子通道导电性进行关闭.
- 这种位点的突变,如GluN1(Y668H),可以导致显著的NMDA受体功能障碍.
- 这些发现将特定的GRIN1变异与潜在的神经疾病联系起来.
相关概念视频
Ligand-Gated Ion Channel Receptor: Gating Mechanism
2.3K
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...
2.3K
Ligand-gated Ion Channels
12.4K
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...
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...
12.4K
Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein
332
Antiepileptic drugs, such as levetiracetam (Keppra) and brivaracetam (Briviact), have emerged as crucial tools in managing epilepsy. These medications exert their therapeutic effects by targeting the synaptic vesicle protein SV2A, a transmembrane glycoprotein primarily found in the brain.
SV2A is a transmembrane glycoprotein located predominantly in the brain, modulating the release of neurotransmitters for neuronal communication. Both levetiracetam and brivaracetam exhibit a high affinity for...
SV2A is a transmembrane glycoprotein located predominantly in the brain, modulating the release of neurotransmitters for neuronal communication. Both levetiracetam and brivaracetam exhibit a high affinity for...
332
Human Genetics
601
Human genetics provides a profound framework for understanding the interplay between genetic predispositions and human psychology. At the heart of this discipline lies the study of how genes influence physical traits, behaviors, and susceptibility to diseases. Each person carries a unique genetic code that subtly or significantly shapes their psychological and behavioral landscape.
The complex relationship between genetics and psychology is observable through common biological components such...
The complex relationship between genetics and psychology is observable through common biological components such...
601
Non-gated Ion Channels
6.8K
Ion channels are specialized proteins on the plasma membrane that allow charged ions to pass down their electrochemical gradient. Their main function is to maintain the membrane potential which is critical for cell viability. These channels are either gated or non-gated and can transport more than a thousand ions within milliseconds for the cellular event to occur.
Compared to the gated ion channels, the non-gated channels, also known as leakage or passive channels, have no gating mechanism....
Compared to the gated ion channels, the non-gated channels, also known as leakage or passive channels, have no gating mechanism....
6.8K
Mechanically-gated Ion Channels
6.4K
Mechanically-gated ion channels are proteins found in eukaryotic and prokaryotic cell membranes that open in response to mechanical stress. Tension, compression, swelling, and shear stress can alter the conformation of the protein, opening a transmembrane channel that allows the passage of ions for signal transmission. In eukaryotes, mechanically-gated channels are distributed in several regions like the neurons, lungs, skin, bladder, and heart, where they play critical roles in numerous...
6.4K


