Klapproth Erik, Kämmerer Susanne, El-Armouche Ali
Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Cell Signal. 2022 Feb;90:110203. doi: 10.1016/j.cellsig.2021.110203. Epub 2021 Nov 22.
Reversible phosphorylation of ion channels and calcium-handling proteins provides precise post-translational regulation of cardiac excitation and contractility. Serine/threonine phosphatases govern dephosphorylation of the majority of cardiac proteins. Accordingly, dysfunction of this regulation contributes to the development and progression of heart failure and atrial fibrillation. On the molecular level, these changes include alterations in the expression level and phosphorylation status of Ca handling and excitation-contraction coupling proteins provoked by dysregulation of phosphatases. The serine/threonine protein phosphatase PP1 is one a major player in the regulation of cardiac excitation-contraction coupling. PP1 essentially impacts on cardiac physiology and pathophysiology via interactions with the cardiac ion channels Cav1.2, NKA, NCX and KCNQ1, sarcoplasmic reticulum-bound Ca handling proteins such as RyR2, SERCA and PLB as well as the contractile proteins MLC2, TnI and MyBP-C. PP1 itself but also PP1-regulatory proteins like inhibitor-1, inhibitor-2 and heat-shock protein 20 are dysregulated in cardiac disease. Therefore, they represent interesting targets to gain more insights in heart pathophysiology and to identify new treatment strategies for patients with heart failure or atrial fibrillation. We describe the genetic and holoenzymatic structure of PP1 and review its role in the heart and cardiac disease. Finally, we highlight the importance of the PP1 regulatory proteins for disease manifestation, provide an overview of genetic models to study the role of PP1 for the development of heart failure and atrial fibrillation and discuss possibilities of pharmacological interventions.
离子通道和钙处理蛋白的可逆磷酸化对心脏的兴奋和收缩性进行精确的翻译后调控。丝氨酸/苏氨酸磷酸酶负责大多数心脏蛋白的去磷酸化。因此，这种调控功能障碍会导致心力衰竭和心房颤动的发生与发展。在分子水平上，这些变化包括因磷酸酶失调而引起的钙处理及兴奋 - 收缩偶联蛋白的表达水平和磷酸化状态的改变。丝氨酸/苏氨酸蛋白磷酸酶PP1是心脏兴奋 - 收缩偶联调控中的主要参与者之一。PP1主要通过与心脏离子通道Cav1.2、NKA、NCX和KCNQ1、与肌浆网结合的钙处理蛋白如RyR2、SERCA和PLB以及收缩蛋白MLC2、TnI和MyBP - C相互作用，从而影响心脏生理和病理生理过程。在心脏疾病中，PP1本身以及像抑制剂 - 1、抑制剂 - 2和热休克蛋白20等PP1调节蛋白都会失调。因此，它们是深入了解心脏病理生理学以及为心力衰竭或心房颤动患者确定新治疗策略的有趣靶点。我们描述了PP1的基因和全酶结构，并综述了其在心脏及心脏疾病中的作用。最后，我们强调了PP1调节蛋白对疾病表现的重要性，概述了用于研究PP1在心力衰竭和心房颤动发生发展中作用的遗传模型，并讨论了药物干预的可能性。
