Compartmentalized cyclic nucleotides have opposing effects on regulation of hypertrophic phospholipase Cε signaling in cardiac myocytes

Nash, Craig; Brown, Loren; Malik, Sundeep; Cheng, Xiaodong; Smrcka, Alan V.

doi:10.1016/j.yjmcc.2018.06.002

Cited by 23 publications

(35 citation statements)

References 39 publications

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“…In previous work we found that either the Epac-selective cAMP analog, cpTOME, or forskolin stimulation of adenylate cyclase, activate PLCε-dependent Golgi PI4P hydrolysis in cardiac myocytes. Surprisingly, the βAR agonist isoproterenol (Iso), does not stimulate Golgi PI4P hydrolysis despite strongly stimulating cAMP production (Nash et al, 2018). As an explanation for this apparent paradox we demonstrated PLCε-dependent PI4P hydrolysis can be controlled by two distinct pools of cAMP delimited by distinct PDE isoforms.…”

Section: Introductionmentioning

confidence: 99%

Golgi localized β1-adrenergic receptors stimulate Golgi PI4P hydrolysis by PLCε to regulate cardiac hypertrophy

Nash

Wei

Irannejad

et al. 2019

eLife

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Increased adrenergic tone resulting from cardiovascular stress leads to development of heart failure, in part, through chronic stimulation of β1 adrenergic receptors (βARs) on cardiac myocytes. Blocking these receptors is part of the basis for β-blocker therapy for heart failure. Recent data demonstrate that G protein-coupled receptors (GPCRs), including βARs, are activated intracellularly, although the biological significance is unclear. Here we investigated the functional role of Golgi βARs in rat cardiac myocytes and found they activate Golgi localized, prohypertrophic, phosphoinositide hydrolysis, that is not accessed by cell surface βAR stimulation. This pathway is accessed by the physiological neurotransmitter norepinephrine (NE) via an Oct3 organic cation transporter. Blockade of Oct3 or specific blockade of Golgi resident β1ARs prevents NE dependent cardiac myocyte hypertrophy. This clearly defines a pathway activated by internal GPCRs in a biologically relevant cell type and has implications for development of more efficacious β-blocker therapies.

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Section: Introductionmentioning

confidence: 99%

Golgi localized β1-adrenergic receptors stimulate Golgi PI4P hydrolysis by PLCε to regulate cardiac hypertrophy

Nash

Wei

Irannejad

et al. 2019

eLife

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“…PDE2 inhibition has been hypothesized to promote PKA-dependent phosphorylation and thereby inhibition of PLCε. Diminished PLCε-induced PI4P hydrolysis in the Golgi apparatus thus abrogates hypertrophic signalling [ 179 ].…”

Section: Role Of Pde2 In Cardiovascular Diseasementioning

confidence: 99%

Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases

Sadek

Cachorro

El‐Armouche

et al. 2020

IJMS

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Phosphodiesterases (PDEs) are the principal superfamily of enzymes responsible for degrading the secondary messengers 3′,5′-cyclic nucleotides cAMP and cGMP. Their refined subcellular localization and substrate specificity contribute to finely regulate cAMP/cGMP gradients in various cellular microdomains. Redistribution of multiple signal compartmentalization components is often perceived under pathological conditions. Thereby PDEs have long been pursued as therapeutic targets in diverse disease conditions including neurological, metabolic, cancer and autoimmune disorders in addition to numerous cardiovascular diseases (CVDs). PDE2 is a unique member of the broad family of PDEs. In addition to its capability to hydrolyze both cAMP and cGMP, PDE2 is the sole isoform that may be allosterically activated by cGMP increasing its cAMP hydrolyzing activity. Within the cardiovascular system, PDE2 serves as an integral regulator for the crosstalk between cAMP/cGMP pathways and thereby may couple chronically adverse augmented cAMP signaling with cardioprotective cGMP signaling. This review provides a comprehensive overview of PDE2 regulatory functions in multiple cellular components within the cardiovascular system and also within various subcellular microdomains. Implications for PDE2- mediated crosstalk mechanisms in diverse cardiovascular pathologies are discussed highlighting the prospective use of PDE2 as a potential therapeutic target in cardiovascular disorders.

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“…Epac1 also promotes spontaneous diastolic Ca 2+ leak via CaMKII-dependent ryanodine receptors (RyR) hyperphosphorylation. Intriguingly, recent works suggested that intracellular β-ARs located at the Golgi could generate a specific pool of cAMP to stimulate a prohypertrophic Epac1/phospholipase C (PLC)ε signalling, which is scaffolded at the nuclear envelope of cardiomyocytes to the muscle-specific A-kinase anchoring (mAKAP) scaffolding protein [65,66] (Figure 2). Other studies demonstrated that an Epac1-PLC signalling could cause protein kinase D (PKD) activation and nuclear Ca 2+ increase via the perinuclear inositol-1,4,5-trisphosphate (IP3) receptor resulting in the activation of CaMKII-dependent epigenetic regulation involving HDAC4 and HDAC5 [7,64,67,68].…”

Section: Epigenetic Regulation Of Epac1 During Cardiac Remodellingmentioning

confidence: 99%

The Epac1 Protein: Pharmacological Modulators, Cardiac Signalosome and Pathophysiology

Bouvet

Blondeau

Lezoualc’h

2019

Cells

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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.

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Compartmentalized cyclic nucleotides have opposing effects on regulation of hypertrophic phospholipase Cε signaling in cardiac myocytes

Cited by 23 publications

References 39 publications

Golgi localized β1-adrenergic receptors stimulate Golgi PI4P hydrolysis by PLCε to regulate cardiac hypertrophy

Golgi localized β1-adrenergic receptors stimulate Golgi PI4P hydrolysis by PLCε to regulate cardiac hypertrophy

Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases

The Epac1 Protein: Pharmacological Modulators, Cardiac Signalosome and Pathophysiology

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