Exchange protein directly activated by cAMP 1 promotes autophagy during cardiomyocyte hypertrophy.

Aims: Stimulation of β-adrenergic receptors (β-AR) increases cAMP production and contributes to the pathogenesis of cardiac hypertrophy and failure through poorly understood mechanisms. We previously demonstrated that Exchange protein directly activated by cAMP 1 (Epac1)-induced hypertrophy in primary cardiomyocytes. Among the mechanisms triggered by cardiac stress, autophagy has been highlighted as a protective or harmful response.

Carabin protects against cardiac hypertrophy by blocking calcineurin, Ras, and Ca2+/calmodulin-dependent protein kinase II signaling.

Background: Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and is regulated by various signaling pathways. However, the molecular mechanisms that negatively regulate these signal transduction pathways remain poorly understood.

Methods And Results: Here, we characterized Carabin, a protein expressed in cardiomyocytes that was downregulated in cardiac hypertrophy and human heart failure.

Epac1 and Epac2 are differentially involved in inflammatory and remodeling processes induced by cigarette smoke.

Cigarette smoke (CS) induces inflammatory responses characterized by increase of immune cells and cytokine release. Remodeling processes, such as mucus hypersecretion and extracellular matrix protein production, are also directly or indirectly induced by CS. Recently, we showed that activation of the exchange protein directly activated by cAMP (Epac) attenuates CS extract-induced interleukin (IL)-8 release from cultured airway smooth muscle cells.

Specific interactions between Epac1, β-arrestin2 and PDE4D5 regulate β-adrenergic receptor subtype differential effects on cardiac hypertrophic signaling.

β1 and β2 adrenergic receptors (βARs) are highly homologous but fulfill distinct physiological and pathophysiological roles. Here we show that both βAR subtypes activate the cAMP-binding protein Epac1, but they differentially affect its signaling. The distinct effects of βARs on Epac1 downstream effectors, the small G proteins Rap1 and H-Ras, involve different modes of interaction of Epac1 with the scaffolding protein β-arrestin2 and the cAMP-specific phosphodiesterase (PDE) variant PDE4D5.

Role of Epac in brain and heart.

Epacs (exchange proteins directly activated by cAMP) are guanine-nucleotide-exchange factors for the Ras-like small GTPases Rap1 and Rap2. Epacs were discovered in 1998 as new sensors for the second messenger cAMP acting in parallel to PKA (protein kinase A). As cAMP regulates many important physiological functions in brain and heart, the existence of Epacs raises many questions regarding their role in these tissues.

Epac enhances excitation-transcription coupling in cardiac myocytes.

Epac is a guanine nucleotide exchange protein that is directly activated by cAMP, but whose cardiac cellular functions remain unclear. It is important to understand cardiac Epac signaling, because it is activated in parallel to classical cAMP-dependent signaling via protein kinase A. In addition to activating contraction, Ca(2+) is a key cardiac transcription regulator (excitation-transcription coupling).

New perspectives in cAMP-signaling modulation.

Cyclic adenosine 3',5'-monophosphate (cAMP) mediates the biological effects of various hormones and neurotransmitters. Stimulation of cardiac β-adrenergic receptors (β-AR) via catecholamines leads to activation of adenylyl cyclases and increases cAMP production to enhance myocardial function. Because many other receptors signaling through cAMP generation exist in cardiac myocytes, a central question is how different hormones induce distinct cellular responses through the same second messenger.

Rap-linked cAMP signaling Epac proteins: compartmentation, functioning and disease implications.

Epac proteins respond to the second messenger cyclic AMP (cAMP) and are activated by Gs coupled receptors. They act as specific guanine nucleotide exchange factors (GEFs) for the small G proteins, Rap1 and Rap2 of the Ras family. A plethora of studies using 8-pCPT-2'-O-Me-cAMP, an Epac agonist, has revealed the importance of these multi-domain proteins in the control of key cellular functions such as cell division, migration, growth and secretion.

Epac activation induces histone deacetylase nuclear export via a Ras-dependent signalling pathway.

Epac (Exchange protein directly activated by cAMP) is a sensor for cAMP and represents a novel mechanism for governing cAMP signalling. Epac is a guanine nucleotide exchange factor (GEF) for the Ras family of small GTPases, Rap. Previous studies demonstrated that, in response to a prolonged beta-adrenergic stimulation Epac induced cardiac myocyte hypertrophy.