The Epac1 Protein: Pharmacological Modulators, Cardiac Signalosome and Pathophysiology

Abstract

The second messenger 3′,5′-cyclic adenosine monophosphate (cAMP) is one of the most important signalling molecules in the heart as it regulates many physiological and pathophysiological processes. In addition to the classical protein kinase A (PKA) signalling route, the exchange proteins directly activated by cAMP (Epac) mediate the intracellular functions of cAMP and are now emerging as a new key cAMP effector in cardiac pathophysiology. In this review, we provide a perspective on recent advances in the discovery of new chemical entities targeting the Epac1 isoform and illustrate their use to study the Epac1 signalosome and functional characterisation in cardiac cells. We summarize the role of Epac1 in different subcompartments of the cardiomyocyte and discuss how cAMP–Epac1 specific signalling networks may contribute to the development of cardiac diseases. We also highlight ongoing work on the therapeutic potential of Epac1-selective small molecules for the treatment of cardiac disorders.

A-Kinase Anchoring Protein 1: Emerging Roles in Regulating Mitochondrial Form and Function in Health and Disease

“…cAMP is synthesized from ATP by a family of adenylyl cyclases, which are regulated by heterotrimeric G proteins or Ca 2+ /calmodulin in response to cell surface receptor signaling. cAMP actions are mediated by two effectors, cAMP-dependent protein kinase (PKA) and the more recently discovered guanylate exchange factor Epac (exchange protein directly activated by cAMP) [3]. cAMP signaling is terminated by the hydrolysis of cAMP to 5 -AMP by a large group of phosphodiesterases, which are themselves highly regulated [4].…”

Special Issue on “New Advances in Cyclic AMP Signalling”—An Editorial Overview

“…This Special Edition highlights the important role that EPAC proteins play in cellular physiology. For example, the manuscript, entitled “Epac1 protein: pharmacological modulators, cardiac signalosome and pathophysiology”, by Bouvet et al [ 35 ] presents an overview of the recent advances in pharmacological tools to target EPAC signaling and it illustrates the role of EAPC1 in cardiomyocytes and how dysregulation of EPAC signaling may contribute to the development of cardiac disease. Indeed, the review by Smith et al [ 8 ] details how PKA and EPAC1 suppresses vascular smooth muscle cell proliferation through cytoskeleton remodelling and proliferation-associated gene expression through TEAD transcription factors, highlighting further potential drug targets for the treatment of restenosis after angioplasty, vein graft intimal thickening, and atherosclerosis [ 8 ].…”

Role of EPAC1 Signalosomes in Cell Fate: Friends or Foes?

“…EPAC1 is also involved in migration, proliferation, and apoptosis in several types of cancers [ 9 , 10 , 11 , 12 ]. The role of EPAC1 in cardiac pathologies such as heart failure and arrhythmias has been characterized using EPAC1 transgenic mouse models, although it remains a matter of discussion [ 13 , 14 ]. Consistent with cAMP compartmentation, EPAC1 is spatially and temporally regulated by scaffolding proteins and its effectors interconnect with other signaling pathways.…”