交通控制:CCR5的联体特异内化和细胞内分布的机制
Siyi Gu1, Svetlana Maurya1, Alexis Lona2
1Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California; Department of Pharmacology, University of California San Diego, La Jolla, California.
Molecular pharmacology
|April 8, 2025
概括
这项研究揭示了不同的连接物如何导致CC化学受体 (CCR) 5在细胞内移动. 了解CCR5贩运为炎症性疾病和艾滋病毒提供了新的治疗策略.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- CC化学因子受体 (CCR) 5对免疫反应至关重要,并与炎症,癌症和艾滋病毒传播有关.
- 像马拉维洛克这样的CCR5抗剂用于HIV,但更广泛的治疗应用受到复杂的CCR5药理的限制.
- 联体诱导的CCR5封存 (细胞内保留) 是一个潜在的治疗点,但潜在的机制仍然不清楚.
研究的目的:
- 系统地比较CCR5对其自然激动剂 (CCL5) 和两种诱导细胞内保留的变体的反应中的贩运动态.
- 阐明控制CCR5在细胞膜上定位的独特细胞机制,而不是细胞内区间.
- 为了确定联结体特异性贩运如何影响CCR5功能和化学激素清理.
主要方法:
- 利用药理学分析,光显微镜和活细胞近距离标记蛋白质组学.
- 通过CCL5及其变体进行刺激后,调查了依赖时间的CCR5贩运.
- 分析了受体内部化,溶酶体降解和戈尔吉/跨戈尔吉网络向.
主要成果:
- 所有测试的化基因因都通过β-止素依赖的,克拉特林介导的内细胞分裂诱导了CCR5的内化,但具有不同的动力学和受体激酶依赖性.
- 观察到明显的依赖于连接体的贩运模式,影响CCR5定位到溶解体和戈尔吉装置.
- 贩运的差异与不同的化学物质清理能力相关.
结论:
- 干特异性相互作用决定了独特的CCR5贩运途径,影响受体功能和细胞信号传递.
- 阐明了细胞内CCR5封存机制,突出了其作为治疗策略的潜力.
- 这项研究为开发针对特定贩运路线的新型CCR5功能抗剂提供了基础.
相关概念视频
Receptor-mediated Endocytosis
5.8K
Receptor-mediated endocytosis is when bulk amounts of specific molecules are imported into a cell after binding to cell surface receptors. The molecules bound to these receptors are taken into the cell through inward folding of the cell surface membrane, which is eventually pinched off into a vesicle within the cell. Structural proteins, such as clathrin, coat the budding vesicle.
Clathrin-Mediated Endocytosis of LDL
One well-characterized example of receptor-mediated endocytosis is the...
Clathrin-Mediated Endocytosis of LDL
One well-characterized example of receptor-mediated endocytosis is the...
5.8K
Activation of Integrins
3.2K
Integrins bind ligands and transmit information from outside the cell to inside or vice-versa through an "outside-in signaling" or "inside-out signaling."
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding...
In "outside-in signaling," external factors in the extracellular space bind to exposed ligand binding sites on integrins. This causes the inactive protein to undergo a conformational change to become active. Integrins are often clustered on the cell membrane. Repetitive and regularly spaced ligand binding...
3.2K
GPCR Desensitization
5.6K
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
5.6K
Internal Receptors
68.8K
Many cellular signals are hydrophilic and therefore cannot pass through the plasma membrane. However, small or hydrophobic signaling molecules can cross the hydrophobic core of the plasma membrane and bind to internal, or intracellular, receptors that reside within the cell. Many mammalian steroid hormones use this mechanism of cell signaling, as does nitric oxide (NO) gas.
68.8K
Intracellular Signaling Affects Focal Adhesions
2.5K
Integrins act both as extracellular input receivers and as intracellular processing activators. As their name suggests, integrins are entirely integrated into the membrane structure. Their hydrophobic membrane-spanning regions interact with the phospholipid bilayer's hydrophobic region. These membrane receptors provide extracellular attachment sites for effectors like hormones and growth factors. They activate intracellular response cascades when their effectors are bound and active.
Some...
Some...
2.5K
Types of Receptors: Internal Receptors
20.3K
Many cellular signals are hydrophilic and cannot pass through the plasma membrane. However, small or hydrophobic signaling molecules can cross the hydrophobic core of the plasma membrane and bind intracellular receptors that reside within the cell cytoplasm or nucleus. Many mammalian steroid hormones and nitric oxide (NO) gas use this cell signaling mechanism.
Similar to membrane-bound receptors, the binding of a ligand to the intracellular receptor of causes a conformational change in the...
Similar to membrane-bound receptors, the binding of a ligand to the intracellular receptor of causes a conformational change in the...
20.3K


