作为成治疗机制的G蛋白失活.
Carlie Neiswanger1, Micaela V Ruiz1, Kandace Kimball1
1Departments of Pharmacology.
Biological psychiatry
|April 6, 2025
概括
纳尔富拉芬和纳尔梅芬导致长期的卡帕阿片类受体 (KOR) 失活,为与压力相关的疾病提供潜在的治疗方法. 这种KOR无活化机制与竞争性抑制不同,对诸如成和抑郁症等疾病具有治疗前景.
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.
背景情况:
- 内源性迪诺芬/卡帕阿片类受体 (KOR) 系统调解压力诱导的性障碍症.
- 科尔抗剂是治疗成,抑郁和精神病的潜在疗法.
- 长期作用的诺比纳尔多芬胺 (norBNI) 类抗体可能通过c-Jun-kinase机制使KORs失活.
研究的目的:
- 查诱导类似于norbinaltorphimine (norBNI) 的卡帕阿片类受体 (KOR) 失活的阿片类联体.
- 调查KOR无活化的治疗潜力,用于因多芬介导的压力障碍.
主要方法:
- 选的阿片类配体对KOR无活化.
- 对纳尔富拉芬和纳尔梅芬用于KOR无活化的评估.
- 评估KOR无活化的性依赖和荷尔蒙影响.
- 对KOR无活化与片受体作用的剂量反应研究.
- 研究KOR无活化对小鼠各种生理反应的影响.
主要成果:
- 纳尔富拉芬和纳尔梅芬在较低的剂量下诱导长期的KOR无活化,而不是对阿片类受体效应所需的.
- 纳尔富拉芬的KOR无活化取决于性别,发生在雌性期或孕激素治疗后.
- 在阿片类药物戒断期间,每天微量服用纳尔富拉芬或纳尔梅芬会积累抑制,阻断参与抗感受,压力厌恶和失调症的KORs.
- 介导尿液和抗作用的KORs不受JNK的调节.
结论:
- 纳尔富拉芬和纳尔梅芬显示出一种新的KOR无活化机制.
- 这些药物具有既定的安全性,可以重新用于治疗因多芬介导的压力障碍.
- 这些发现表明了对成,抑郁和精神病的新治疗途径.
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
13.5K
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
5.6K
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
Activation and Inactivation of G Proteins
6.5K
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...
6.5K
GPCRs Regulate Adenylyl Cylase Activity
5.1K
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...
5.1K
G-protein Coupled Receptors
113.3K
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.
113.3K
G Protein-coupled Receptors
10.9K
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...
10.9K
Ligand-Gated Ion Channel Receptor: Gating Mechanism
2.0K
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...
2.0K
