对听力来说,LRRC8/VRAC调节音量的离子通道对于听力至关重要
Deborah A Knecht1, Mariia Zeziulia2, Mit B Bhavsar3
1Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany; Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany.
The Journal of biological chemistry
|June 5, 2024
概括
音量调节的离子通道 (VRAC) 对听力至关重要,因为其破坏会影响离子恒温和基本通道,从而导致小鼠的耳退化和聋.
科学领域:
- 内耳生理学 内耳生理学
- 分子生物学分子生物学
- 耳毒性研究研究
背景情况:
- 耳离子稳定对于听力至关重要,而离子通道的突变会导致聋.
- 虽然已知ClC-K/barttin通道会影响听力,但内耳中的其他离子通道尚未研究.
- 体积调节的离子通道 (VRAC) 运输化物,代谢物和药物,但其在内耳中的作用尚不清楚.
研究的目的:
- 为了研究LRRC8子单元的分布,形成VRAC,在尾.
- 通过切除其子单元来探索VRAC在听力和内耳功能中的生理作用.
- 了解VRAC对耳离子传输的贡献及其与耳毒性的潜在联系.
主要方法:
- 评估了所有五个LRRC8子单位的内分布.
- 产生了具有破坏LRRC8A,LRRC8D和LRRC8E子单元的转基因小鼠.
- 在淘汰的小鼠中分析了耳结构,听觉功能和内耳潜力.
- 研究了像Kir4.1这样的关键离子通道的表达和代谢产物的作用.
主要成果:
- 所有LRRC8子单元都表达在感官毛细胞中;LRRC8A,D和E都存在于血管中.
- 在小鼠中,LRRC8A或LRRC8D/E的破坏导致了耳退化和先天性聋.
- 失去VRAC功能严重降低了内耳潜力,并导致Kir4.1表达的显著下降.
- 与ClC-K/barttin不同的是,VRAC中断导致Kir4.1几乎完全丧失,可能是由于代谢物运输的改变.
结论:
- 由LRRC8子单元组成的VRAC在维护耳结构和功能方面发挥着至关重要的作用,这对听力至关重要.
- VRAC对于产生内耳潜能是必要的,部分原因是通过其对Kir4.1表达和代谢物运输的调节.
- 这些发现扩大了我们对耳离子运输机制及其对听力和药物诱导的耳毒性影响的理解.
相关概念视频
01:22Hair Cells
40.2K
Hair cells are the sensory receptors of the auditory system—they transduce mechanical sound waves into electrical energy that the nervous system can understand. Hair cells are located in the organ of Corti within the cochlea of the inner ear, between the basilar and tectorial membranes. The actual sensory receptors are called inner hair cells. The outer hair cells serve other functions, such as sound amplification in the cochlea, and are not discussed in detail here.
40.2K
01:15Auditory Pathway
5.4K
Auditory pathways constitute the complex neural circuits responsible for transmitting and interpreting auditory information from the peripheral auditory system to the brain. Sound waves are initially captured by the outer ear, funneled through the ear canal, and reach the tympanic membrane (eardrum). These vibrations are transmitted via the middle ear's ossicles to the inner ear's cochlea.
When viewed cross-sectionally, the cochlea reveals the scala vestibuli and scala tympani flanking...
When viewed cross-sectionally, the cochlea reveals the scala vestibuli and scala tympani flanking...
5.4K
01:16Anatomy of the Ear
8.3K
Auditory sensation, commonly called hearing, involves the transformation of sonic waves into neural impulses facilitated by the structures of the auditory organ. The prominent, flesh-like structure on the side of the head, called the auricle, directs sound waves towards the auditory canal. The auricle is often mislabeled as the pinna, a term more aligned with mobile structures like a feline's external ear. The auditory canal penetrates the cranium via the external auditory meatus of the...
8.3K
01:13The Cochlea
44.7K
The cochlea is a coiled structure in the inner ear that contains hair cells—the sensory receptors of the auditory system. Sound waves are transmitted to the cochlea by small bones attached to the eardrum called the ossicles, which vibrate the oval window that leads to the inner ear. This causes fluid in the chambers of the cochlea to move, vibrating the basilar membrane.
44.7K
01:26Voltage-gated Ion Channels
8.2K
Voltage-gated ion channels are transmembrane proteins that open and close in response to changes in the membrane potential. They are present on the membranes of all electrically excitable cells such as neurons, heart, and muscle cells.
Generally, all voltage-gated ion channels have a 'voltage-sensing domain' that spans the lipid bilayer. The charged residues in the sensor move in response to the membrane potential changes that open the channel allowing ions movement. There are several...
Generally, all voltage-gated ion channels have a 'voltage-sensing domain' that spans the lipid bilayer. The charged residues in the sensor move in response to the membrane potential changes that open the channel allowing ions movement. There are several...
8.2K
01:31Hearing
52.0K
When we hear a sound, our nervous system is detecting sound waves—pressure waves of mechanical energy traveling through a medium. The frequency of the wave is perceived as pitch, while the amplitude is perceived as loudness.
52.0K