对弱酸激活TRPV2的功能和结构见解
Ferdinand M Haug1, Ruth A Pumroy2, Akshay Sridhar3
1Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, 30625, Hannover, Germany.
The EMBO journal
|April 26, 2024
概括
弱碳酸通过透细胞膜来激活和敏感TRPV2通道. 在TRPV2中的特定残留物对这种弱酸敏感性至关重要,影响细胞反应.
科学领域:
- 分子生物学分子生物学
- 离子通道生理学 离子通道生理学
- 生物化学 生物化学
背景情况:
- 暂时受体潜能 (TRP) 离子通道在维持酸稳态中发挥作用.
- 通过TRP通道感知和响应弱酸的特定机制尚未完全理解.
研究的目的:
- 研究TRPV2在感知弱碳酸中的作用.
- 阐明TRPV2.2弱酸激活和敏感化的基础分子机制.
- 确定TRPV2对弱酸反应中的关键残留物和结构特征.
主要方法:
- 利用无细胞的内外补丁电生理学研究TRPV2通道活性.
- 采用冷电子显微镜 (cryo-EM) 在乙酸存在下确定大鼠TRPV2 (rTRPV2) 的结构.
- 在rTRPV2结构上进行了分子动力学模拟和局部定向突变发生,以验证已识别的残留物的功能作用.
主要成果:
- 证明弱碳酸 (乙酸,乳酸,CO2) 激活和敏感TRPV2通道,需要通过膜.
- 确定了细胞外 (Glu495,Glu561) 和细胞内 (His521) 标化残留物,对弱酸敏感性至关重要,通过突变发生证实了这一点.
- 表明孔隙残留物Glu609通过细胞外介导抑制弱酸诱导电流,并且TRPV2表达增加了细胞毒性.
结论:
- 弱酸通过一种依赖透的机制作为TRPV2通道功能的内源调节剂.
- 特定的可定位残留物和毛孔层残留物对于TRPV2对弱酸和抑制的反应至关重要.
- 弱酸激活TRPV2有助于细胞细胞毒性,突出其在酸调节中的生理相关性.
相关概念视频
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
Acid Strength and Molecular Structure
30.9K
Binary Acids and Bases
In the absence of any leveling effect, the acid strength of binary compounds of hydrogen with nonmetals (A) increases as the H-A bond strength decreases down a group in the periodic table. For group 17, the order of increasing acidity is HF < HCl < HBr < HI. Likewise, for group 16, the order of increasing acid strength is H2O < H2S < H2Se < H2Te. Across a row in the periodic table, the acid strength of binary hydrogen compounds increases with...
In the absence of any leveling effect, the acid strength of binary compounds of hydrogen with nonmetals (A) increases as the H-A bond strength decreases down a group in the periodic table. For group 17, the order of increasing acidity is HF < HCl < HBr < HI. Likewise, for group 16, the order of increasing acid strength is H2O < H2S < H2Se < H2Te. Across a row in the periodic table, the acid strength of binary hydrogen compounds increases with...
30.9K
Acidity and Basicity of Carboxylic Acid Derivatives
3.4K
Carboxylic acids are the strongest among organic acids, as they readily lose the hydroxyl proton to form a resonance-stabilized carboxylate ion. In comparison, the acid derivatives lack acidic hydrogens directly attached to a functional group. In these compounds, the acidic nature arises from their ability to lose α hydrogens, making them weakly acidic.
The relative acidic strength of the derivatives can be explained based on the extent of resonance stabilization of the conjugate base. The...
The relative acidic strength of the derivatives can be explained based on the extent of resonance stabilization of the conjugate base. The...
3.4K
Voltage-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
Thermosensation
30.4K
Peripheral thermosensation is the perception of external temperature. A change in temperature (on the surface of the skin and other tissues) is detected by a family of temperature-sensitive ion channels called Transient Receptor Potential, or TRP, receptors. These receptors are located on free nerve endings. Those detecting cold temperatures are closer to the surface of the skin than the nerve endings detecting warmth. These thermoTRP channels, while temperature selective, have relatively...
30.4K
Local Anesthetics: Chemistry and Structure-Activity Relationship
4.4K
Local anesthetics (LAs) are drugs that induce a temporary loss of sensation in a limited body area, preventing pain. Cocaine was the first local anesthetic discovered in the late 19th century. Cocaine is a benzoic acid ester obtained from the leaves of coca shrubs and was often used for its psychotropic effects. Cocaine was first isolated in 1860 by Albert Niemann. Sigmund Freud studied the physiological actions of cocaine. Carl Koller later introduced it into clinical practice in 1884 as a...
4.4K


