作为成治疗机制的G蛋白失活.
Carlie Neiswanger1, Micaela V Ruiz1, Kandace Kimball1
1Departments of Pharmacology, Seattle, WA.
bioRxiv : the preprint server for biology
|January 7, 2025
概括
以前在人类中使用的纳尔富拉芬和纳尔梅芬可以长时间禁用卡帕阿片类受体 (KORs). 这种KOR无活化可能为与压力相关的疾病,如成和抑郁症提供新的治疗方法.
科学领域:
- 神经科学是一个神经科学.
- 药理学 药理学是指药理学的学科.
- 分子生物学分子生物学
背景情况:
- 大脑的迪诺芬/卡帕阿片类受体 (KOR) 系统与压力诱导的性障碍有关.
- 科尔抗剂在治疗成,抑郁和精神病方面表现有前途.
- 长效的KOR抗剂如norBNI可能通过cJun-kinase介导的失活作用,而不是竞争性抑制.
研究的目的:
- 为了识别诱导norBNI类 KOR 失活的新型阿片类配体.
- 研究这些配体的潜在治疗应用.
主要方法:
- 选阿片类配体的KOR无活化特性.
- 在剂量显著低于影响类阿片受体的剂量时对KOR无活化的评估.
- 在 fentanyl 戒断和压力诱导的厌恶的小鼠模型中对 nalfurafine 和 nalmefene 的评估.
主要成果:
- 发现纳尔富拉芬 (G偏向的KOR激动剂) 和纳尔梅芬 (KOR部分激动剂) 诱导长期的KOR无活化.
- 对于这两种联结体来说,KOR无活化发生在比mu阿片类受体效应低10-100倍的剂量下.
- 在小鼠中,每日微剂量纳尔富拉芬或纳尔梅芬阻断了KORs,减轻了压力诱导的厌恶,并在芬太尼戒断期间减少了厌恶.
结论:
- 纳尔富拉芬和纳尔梅芬可以产生持续的KOR无活化,类似于norBNI类抗剂.
- 这些配体具有既定的人类安全概况,可以重新用于治疗因多芬介导的压力障碍.
- 这些发现表明,通过准KOR失活来治疗成,抑郁和精神病的潜在治疗策略.
更多相关视频
07:16Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
13.6K
07:41A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
8.8K
相关概念视频
GPCR Desensitization
5.8K
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...
5.8K
Activation and Inactivation of G Proteins
6.7K
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
6.7K
GPCRs Regulate Adenylyl Cylase Activity
5.3K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
5.3K
G-protein Coupled Receptors
115.6K
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
115.6K
G Protein-coupled Receptors
11.3K
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
11.3K
Ligand-Gated Ion Channel Receptor: Gating Mechanism
2.1K
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...
2.1K
