Lymperopoulos Anastasios, Borges Jordana I, Stoicovy Renee A
Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328-2018, USA.
Pharmaceutics. 2024 May 22;16(6):693. doi: 10.3390/pharmaceutics16060693.
Glucagon-like peptide-1 (GLP-1) is a multifunctional incretin hormone with various physiological effects beyond its well-characterized effect of stimulating glucose-dependent insulin secretion in the pancreas. An emerging role for GLP-1 and its receptor, GLP-1R, in brain neuroprotection and in the suppression of inflammation, has been documented in recent years. GLP-1R is a G protein-coupled receptor (GPCR) that couples to Gs proteins that stimulate the production of the second messenger cyclic 3',5'-adenosine monophosphate (cAMP). cAMP, acting through its two main effectors, protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac), exerts several anti-inflammatory (and some pro-inflammatory) effects in cells, depending on the cell type. The present review discusses the cAMP-dependent molecular signaling pathways elicited by the GLP-1R in cardiomyocytes, cardiac fibroblasts, central neurons, and even in adrenal chromaffin cells, with a particular focus on those that lead to anti-inflammatory effects by the GLP-1R. Fully elucidating the role cAMP plays in GLP-1R's anti-inflammatory properties can lead to new and more precise targets for drug development and/or provide the foundation for novel therapeutic combinations of the GLP-1R agonist medications currently on the market with other classes of drugs for additive anti-inflammatory effect.
胰高血糖素样肽-1（GLP-1）是一种多功能肠促胰岛素激素，除了其在胰腺中刺激葡萄糖依赖性胰岛素分泌这一已被充分了解的作用外，还具有多种生理效应。近年来，已有文献记载GLP-1及其受体GLP-1R在脑保护和炎症抑制方面的新作用。GLP-1R是一种G蛋白偶联受体（GPCR），它与Gs蛋白偶联，刺激第二信使环3',5'-腺苷单磷酸（cAMP）的产生。cAMP通过其两个主要效应器，蛋白激酶A（PKA）和直接由cAMP激活的交换蛋白（Epac）发挥作用，根据细胞类型的不同，在细胞中产生多种抗炎（以及一些促炎）作用。本综述讨论了GLP-1R在心肌细胞、心脏成纤维细胞、中枢神经元甚至肾上腺嗜铬细胞中引发的cAMP依赖性分子信号通路，特别关注那些导致GLP-1R产生抗炎作用的信号通路。充分阐明cAMP在GLP-1R抗炎特性中所起的作用，可为药物研发带来新的、更精确的靶点，和/或为目前市场上的GLP-1R激动剂药物与其他类药物联合使用以产生附加抗炎效果提供新的治疗组合基础。
