在代谢重要细胞类型中通过β-阿雷斯调节GLP-1和葡萄糖受体功能
Liu Liu1, Misbah Rashid1, Jürgen Wess1
1Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, United States.
Biochemistry
|February 21, 2025
概括
类似葡萄糖-1 (GLP-1) 和葡萄糖 (GCG) 通过受体调节新陈代谢. β-arrestin (βarr1/βarr2) 调节这些途径,影响糖尿病和肥胖的药物开发.
科学领域:
- 内分泌学和新陈代谢学
- 分子药理学分子药理学
- 细胞信号传递 细胞信号传递
背景情况:
- 类似葡萄糖-1 (GLP-1) 和葡萄糖 (GCG) 是葡萄糖和能量恒温的关键调节剂.
- 这些激素通过G蛋白结合受体 (GLP-1Rs和GCGRs) 发出信号,主要激活Gs蛋白并增加cAMP.
- 受体激活还招募β-arrestin-1和-2 (βarr1/βarr2),它们终止G蛋白信号传递,并作为独立的信号节点.
研究的目的:
- 审查βarr1和βarr2在GLP-1Rs和GCGRs调节的代谢功能中的作用.
- 讨论GLP-1R激活剂和双GLP-1R/GCGR激活剂的治疗影响.
- 探索偏向激动剂的潜力,这些激动剂选择性地准G蛋白信号传递而不是β-arrestin招募.
主要方法:
- 文献综述综合了关于GLP-1R和GCGR信号传导的研究.
- 分析β-arrestin招募在受体脱敏和信号传递中的作用.
- 评估针对这些途径的当前和新兴治疗策略.
主要成果:
- βarr1和βarr2在调节GLP-1R和GCGR信号通路方面发挥着至关重要的作用.
- GLP-1R激动剂是糖尿病和肥胖症的确立治疗方法.
- 双重激动剂和G蛋白偏差激动剂显示出增强治疗疗效的希望.
结论:
- β-停滞剂的招募是GLP-1R和GCGR信号结果的关键决定因素.
- 向β-阿雷斯相互作用为代谢性疾病提供了新的治疗机会.
- 偏向性激动剂的开发可能会导致更有效的治疗方法,潜在的副作用更少.
相关概念视频
Hormones Regulating Blood Glucose
3.0K
Insulin is released by beta cells of the pancreas when blood glucose levels are high. It facilitates glucose absorption and utilization in insulin-dependent cells with insulin receptors on their plasma membranes. Insulin promotes glucose uptake by increasing the number of glucose transport proteins in the cell membrane, allowing glucose to enter the cell. As a result, glucose utilization and ATP production are enhanced.
In addition to accelerating glucose uptake and utilization, insulin has...
In addition to accelerating glucose uptake and utilization, insulin has...
3.0K
Glucagon-like Receptor Agonists
291
Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
291
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
Glucose Homeostasis: Pancreatic Islets and Insulin Secretion
1.1K
The pancreatic islets comprising only 1%-2% of the volume are highly vascularized and innervated mini-organs. They contain five endocrine cell types, including β cells that secrete insulin, which is synthesized as a single polypeptide chain, preproinsulin, processed to proinsulin, and finally to insulin and C-peptide. This process is complex and regulated, involving the Golgi complex, the endoplasmic reticulum, and the secretory granules of the β cell.
Insulin and C-peptide are...
Insulin and C-peptide are...
1.1K
Insulin: The Receptor and Signaling Pathways
1.1K
Insulin action is mediated through a receptor tyrosine kinase, akin to the IGF-1 receptor. The number of receptors per cell varies significantly, from 40 on erythrocytes to 300,000 on adipocytes and hepatocytes. The insulin receptor consists of linked α/β subunit dimers, forming a heterotetramer glycoprotein with two extracellular α subunits and two β subunits spanning the membrane. The α subunits inhibit the inherent tyrosine kinase activity of the β subunits, but...
1.1K
Glucose Homeostasis: Regulation of Blood Glucose
1.4K
Carbohydrates consumed through foods are converted into glucose, a crucial energy source for the body. In the prandial state, high blood glucose levels stimulate the secretion of insulin from the pancreas. Insulin inhibits hepatic glucose production and stimulates glucose uptake and metabolism by muscle and adipose tissue. The excess glucose is converted into glycogen and stored in the liver and muscles.
During fasting, when blood glucose levels are low, the pancreas secretes glucagon. it...
During fasting, when blood glucose levels are low, the pancreas secretes glucagon. it...
1.4K


