Identification of A Novel Class of Benzofuran Oxoacetic Acid-Derived Ligands that Selectively Activate Cellular EPAC1

Myocardial stress and injury invariably promote remodeling of the cardiac tissue, which is associated with cardiomyocyte death and development of fibrosis. The fibrotic process is initially triggered by the differentiation of resident cardiac fibroblasts into myofibroblasts. These activated fibroblasts display increased proliferative capacity and secrete large amounts of extracellular matrix. Uncontrolled myofibroblast activation can thus promote heart stiffness, cardiac dysfunction, arrhythmias, and progression to heart failure. Despite the well-established role of myofibroblasts in mediating cardiac disease, our current knowledge on how signaling pathways promoting fibrosis are regulated and coordinated in this cell type is largely incomplete. In this respect, cyclic adenosine monophosphate (cAMP) signaling acts as a major modulator of fibrotic responses activated in fibroblasts of injured or stressed hearts. In particular, accumulating evidence now suggests that upstream cAMP modulators including G protein-coupled receptors, adenylyl cyclases (ACs), and phosphodiesterases (PDEs); downstream cAMP effectors such as protein kinase A (PKA) and the guanine nucleotide exchange factor Epac; and cAMP signaling organizers such as A-kinase anchoring proteins (AKAPs) modulate a variety of fundamental cellular processes involved in myocardial fibrosis including myofibroblast differentiation, proliferation, collagen secretion, and invasiveness. The current review will discuss recent advances highlighting the role of cAMP and AKAP-mediated signaling in regulating pathophysiological responses controlling cardiac fibrosis.

Section: Exchange Protein Activated By Campmentioning

confidence: 99%

The Role of Cyclic AMP Signaling in Cardiac Fibrosis

Delaunay

Osman

Kaiser

et al. 2019

“…The potency and the specificity shown towards Epac1 positions 8-CPT as the gold standard ligand for Epac1 activation in vitro and in vivo. However, other compounds are being developed; the first non-nucleotide agonist of Epac1, I942, for example, was isolated by Beck and collaborators (2019) [ 93 ]. Structural analysis showed that I942 was capable of interacting with the CNB domain of both Epac1 and Epac2, but it displayed partial agonist properties only towards Epac1 [ 93 ].…”

Section: Role Of Epac1 In Cardiac Pathophysiologymentioning

confidence: 99%

“…However, other compounds are being developed; the first non-nucleotide agonist of Epac1, I942, for example, was isolated by Beck and collaborators (2019) [ 93 ]. Structural analysis showed that I942 was capable of interacting with the CNB domain of both Epac1 and Epac2, but it displayed partial agonist properties only towards Epac1 [ 93 ]. The group of Yarwood performed systematic modifications on I942 and then structure–activity relationship studies and found four new compounds (25e, 25f, 25n, and 25u) that showed better specificity and higher activity for Epac1 [ 94 ].…”

Section: Role Of Epac1 In Cardiac Pathophysiologymentioning

confidence: 99%

GRKs and Epac1 Interaction in Cardiac Remodeling and Heart Failure

Laudette

Formoso

Lezoualc’h

2021

β-adrenergic receptors (β-ARs) play a major role in the physiological regulation of cardiac function through signaling routes tightly controlled by G protein-coupled receptor kinases (GRKs). Although the acute stimulation of β-ARs and the subsequent production of cyclic AMP (cAMP) have beneficial effects on cardiac function, chronic stimulation of β-ARs as observed under sympathetic overdrive promotes the development of pathological cardiac remodeling and heart failure (HF), a leading cause of mortality worldwide. This is accompanied by an alteration in cAMP compartmentalization and the activation of the exchange protein directly activated by cAMP 1 (Epac1) signaling. Among downstream signals of β-ARs, compelling evidence indicates that GRK2, GRK5, and Epac1 represent attractive therapeutic targets for cardiac disease. Here, we summarize the pathophysiological roles of GRK2, GRK5, and Epac1 in the heart. We focus on their signalosome and describe how under pathological settings, these proteins can cross-talk and are part of scaffolded nodal signaling systems that contribute to a decreased cardiac function and HF development.

“…Another non-cyclic nucleotide, SY009 agonist was isolated by ultra HTS in a library of 350,000 compounds. SY009 is chemically distinct from I942 and displays higher selectivity for EPAC1 over EPAC2 and PKA [ 36 ]. Subsequent studies must be performed to investigate the functional effects of these compounds.…”

Section: Epac1 Pharmacological Modulatorsmentioning

confidence: 99%

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

Formoso

Lezoualc’h

Mialet‐Perez

2020

The compartmentation of signaling processes is accomplished by the assembly of protein complexes called signalosomes. These signaling platforms colocalize enzymes, substrates, and anchoring proteins into specific subcellular compartments. Exchange protein directly activated by cAMP 1 (EPAC1) is an effector of the second messenger, 3′,5′-cyclic adenosine monophosphate (cAMP) that is associated with multiple roles in several pathologies including cardiac diseases. Both EPAC1 intracellular localization and molecular partners are key players in the regulation of cell fate, which may have important therapeutic potential. In this review, we summarize the recent findings on EPAC1 structure, regulation, and pharmacology. We describe the importance of EPAC1 subcellular distribution in its biological action, paying special attention to its nuclear localization and mechanism of action leading to cardiomyocyte hypertrophy. In addition, we discuss the role of mitochondrial EPAC1 in the regulation of cell death. Depending on the cell type and stress condition, we present evidence that supports either a protective or detrimental role of EPAC1 activation.