Slika Hasan, Mansour Hadi, Nasser Suzanne A, Shaito Abdullah, Kobeissy Firas, Orekhov Alexander N, Pintus Gianfranco, Eid Ali H
Department of Pharmacology and Toxicology, American University of Beirut, Beirut, P.O. Box 11-0236, Lebanon.
School of Medicine, Keele University, UK.
Eur J Pharmacol. 2023 Apr 15;945:175645. doi: 10.1016/j.ejphar.2023.175645. Epub 2023 Mar 7.
In 1957, cyclic adenosine monophosphate (cAMP) was identified as the first secondary messenger, and the first signaling cascade discovered was the cAMP-protein kinase A (PKA) pathway. Since then, cAMP has received increasing attention given its multitude of actions. Not long ago, a new cAMP effector named exchange protein directly activated by cAMP (Epac) emerged as a critical mediator of cAMP's actions. Epac mediates a plethora of pathophysiologic processes and contributes to the pathogenesis of several diseases such as cancer, cardiovascular disease, diabetes, lung fibrosis, neurological disorders, and others. These findings strongly underscore the potential of Epac as a tractable therapeutic target. In this context, Epac modulators seem to possess unique characteristics and advantages and hold the promise of providing more efficacious treatments for a wide array of diseases. This paper provides an in-depth dissection and analysis of Epac structure, distribution, subcellular compartmentalization, and signaling mechanisms. We elaborate on how these characteristics can be utilized to design specific, efficient, and safe Epac agonists and antagonists that can be incorporated into future pharmacotherapeutics. In addition, we provide a detailed portfolio for specific Epac modulators highlighting their discovery, advantages, potential concerns, and utilization in the context of clinical disease entities.
1957年，环磷酸腺苷（cAMP）被确定为首个第二信使，而发现的首个信号级联反应是cAMP - 蛋白激酶A（PKA）途径。从那时起，鉴于cAMP的多种作用，它受到了越来越多的关注。不久前，一种名为cAMP直接激活的交换蛋白（Epac）的新型cAMP效应器成为cAMP作用的关键介质。Epac介导大量病理生理过程，并促成多种疾病的发病机制，如癌症、心血管疾病、糖尿病、肺纤维化、神经疾病等。这些发现强烈强调了Epac作为一个易于处理的治疗靶点的潜力。在这种背景下，Epac调节剂似乎具有独特的特性和优势，并有望为多种疾病提供更有效的治疗方法。本文对Epac的结构、分布、亚细胞区室化和信号传导机制进行了深入剖析和分析。我们阐述了如何利用这些特性来设计可纳入未来药物治疗的特异性、高效且安全的Epac激动剂和拮抗剂。此外，我们提供了一份特定Epac调节剂的详细清单，突出了它们在临床疾病实体背景下的发现、优势、潜在问题及应用。
