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Cyclic AMP/PKA/Epac Signaling in Health and Disease

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (15 June 2022) | Viewed by 26620

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Special Issue Editors

Prof. Dr. M.-Saadeh Suleiman

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Guest Editor

Bristol Medical School, University of Bristol, Bristol Royal Infirmary, Bristol BS2 8HW, UK
Interests: cardioprotection; cardioplegia; cardiac remodeling post-acute infarction; molecular changes in diseased heart; ischemia; mitochondria; calcium
Special Issues, Collections and Topics in MDPI journals

Dr. Igor Khaliulin

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Guest Editor

1. Bristol Medical School (THS), Faculty of Health Sciences, University of Bristol, Bristol Royal Infirmary, Upper Maudlin Street, Bristol BS2 8HW, UK
2. Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
Interests: cardiac physiology; neurophysiology; cyclic AMP/PKA/Epac signaling

Special Issue Information

Dear Colleagues,

Cellular signaling associated with cAMP (cyclic AMP) and its target proteins PKA (protein kinase A) and Epac (guanine nucleotide exchange protein directly activated by cAMP) is important in regulating the function of various cell types including those in the cardiovascular, respiratory, excretory, brain, and other systems. The key issues related to cAMP signaling particularly in disease and prevention, remain unanswered or not fully understood. For example, the interaction between PKA and Epac pathways and their interplay with calcium regulation, oxidative stress, and the mitochondria. A major advance in this area has been the availability of cell-permeable cAMP analogues, which have been used to elucidate relevant cellular activities and to demonstrate protection against pathologies. Nonetheless, more work is needed to understand the exact role PKA and different Epac isoforms as well as their expression/cellular distribution in different cell types.

This Special Issue aims to update the current knowledge on the role of cAMP/PKA/Epac signaling in different cell types and to integrate this information to better understand its role in health and disease. This could be related to virtually any pathological condition in different cells, organs, and systems. It is anticipated that such knowledge will help in formulating novel therapeutic interventions that target this signaling pathway.

We look forward to your contributions.

Prof. Dr. M.-Saadeh Suleiman
Dr. Igor Khaliulin
Guest Editors

Manuscript Submission Information

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Keywords

PKA
Epac
cAMP
cardiovascular diseases
renal vascular diseases
cerebrovascular diseases
oxidative stress
mitochondria
calcium
cAMP analougues

Published Papers (6 papers)

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Research

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16 pages, 2905 KiB

Open AccessArticle

MAGED2 Is Required under Hypoxia for cAMP Signaling by Inhibiting MDM2-Dependent Endocytosis of G-Alpha-S

by Elie Seaayfan, Sadiq Nasrah, Lea Quell, Maja Kleim, Stefanie Weber, Hemmo Meyer, Kamel Laghmani and Martin Kömhoff

Cells 2022, 11(16), 2546; https://doi.org/10.3390/cells11162546 - 16 Aug 2022

Cited by 6 | Viewed by 4072

Abstract

Mutations in MAGED2 cause transient Bartter syndrome characterized by severe renal salt wasting in fetuses and infants, which leads to massive polyhydramnios causing preterm labor, extreme prematurity and perinatal death. Notably, this condition resolves spontaneously in parallel with developmental increase in renal oxygenation. MAGED2 interacts with G-alpha-S (Gαs). Given the role of Gαs in activating adenylyl cyclase at the plasma membrane and consequently generating cAMP to promote renal salt reabsorption via protein kinase A (PKA), we hypothesized that MAGED2 is required for this signaling pathway under hypoxic conditions such as in fetuses. Consistent with that, under both physical and chemical hypoxia, knockdown of MAGED2 in renal (HEK293) and cancer (HeLa) cell culture models caused internalization of Gαs, which was fully reversible upon reoxygenation. In contrast to Gαs, cell surface expression of the β2-adrenergic receptor, which is coupled to Gαs, was not affected by MAGED2 depletion, demonstrating specific regulation of Gαs by MAGED2. Importantly, the internalization of Gαs due to MAGED2 deficiency significantly reduced cAMP generation and PKA activity. Interestingly, the internalization of Gαs was blocked by preventing its endocytosis with dynasore. Given the role of E3 ubiquitin ligases, which can be regulated by MAGE-proteins, in regulating endocytosis, we assessed the potential role of MDM2-dependent ubiquitination in MAGED2 deficiency-induced internalization of Gαs under hypoxia. Remarkably, MDM2 depletion or its chemical inhibition fully abolished Gαs-endocytosis following MAGED2 knockdown. Moreover, endocytosis of Gαs was also blocked by mutation of ubiquitin acceptor sites in Gαs. Thus, we reveal that MAGED2 is essential for the cAMP/PKA pathway under hypoxia to specifically regulate Gαs endocytosis by blocking MDM2-dependent ubiquitination of Gαs. This may explain, at least in part, the transient nature of Bartter syndrome caused by MAGED2 mutations and opens new avenues for therapy in these patients. Full article

(This article belongs to the Special Issue Cyclic AMP/PKA/Epac Signaling in Health and Disease)

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11 pages, 2717 KiB

Open AccessArticle

Distinct PKA Signaling in Cytosolic and Mitochondrial Compartments in Electrically Paced Atrial Myocytes

by Noa Kirschner Peretz, Sofia Segal, Ido Weiser-Bitoun and Yael Yaniv

Cells 2022, 11(14), 2261; https://doi.org/10.3390/cells11142261 - 21 Jul 2022

Cited by 1 | Viewed by 1772

Abstract

Protein kinase A (PKA) is a key nodal signaling molecule that regulates a wide range of cellular functions in the cytosol and mitochondria. The distribution of A-kinase anchoring proteins that tether PKA, the local interaction with degradation molecules, and regulation by Ca²⁺, may lead to distinct spatiotemporal cAMP/PKA signaling in these compartments. In this work, FRET-based sensors were used to investigate PKA signaling in the cytosol, outer mitochondrial membrane (OMM), and mitochondrial matrix (MM) and its crosstalk with Ca²⁺ in response to electrical stimulation of cultured rabbit atrial cells. A gradual decrease in PKA activity eliminating the ability of the atrial cells to respond to physiological electrical stimulation, was observed upon treatment of cells with H-89. Chelation of intracellular Ca²⁺ by BAPTA reduced PKA activity and diminished its response to forskolin, an AC stimulator. Under basal conditions, PKA activity in response to forskolin was lower in the OMM compared to the cytosol and MM. In response to electrical stimulation in the presence of ISO, distinct compartmentalization of PKA activity was observed, with higher activity in the cytosol and MM than in the OMM. Thus, distinct Ca²⁺-dependent spatiotemporal cAMP/PKA signaling exists in atrial cells, likely mediating its excitation and mitochondrial function. Full article

(This article belongs to the Special Issue Cyclic AMP/PKA/Epac Signaling in Health and Disease)

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20 pages, 5627 KiB

Open AccessArticle

Cyclic-AMP Increases Nuclear Actin Monomer Which Promotes Proteasomal Degradation of RelA/p65 Leading to Anti-Inflammatory Effects

by Joseph W. Hawkins, Madeleine C. McNeill, Reza Ebrahimighaei, Harry H. Mellor, Andrew C. Newby and Mark Bond

Cells 2022, 11(9), 1414; https://doi.org/10.3390/cells11091414 - 21 Apr 2022

Cited by 2 | Viewed by 1981

Abstract

The second messenger, cAMP has potent immunosuppressive and anti-inflammatory actions. These have been attributed, in part, to the ability of cAMP-induced signals to interfere with the function of the proinflammatory transcription factor Nuclear Factor-kappa B (NF-κB). However, the mechanisms underlying the modulation of NF-κB activity by cAMP remain unclear. Here we demonstrate an important role for cAMP-mediated increase in nuclear actin monomer levels in inhibiting NF-κB activity. Elevated cAMP or forced expression of a nuclear localised polymerisation defective actin mutant (NLS-Actin_R62D) inhibited basal and TNFα induced mRNA levels of NF-κB-dependent genes and NF-κB-dependent reporter gene activity. Elevated cAMP or NLS-Actin_R62D did not affect NF-κB nuclear translocation but did reduce total cellular and nuclear RelA/p65 levels. Preventing the cAMP-induced increase in nuclear actin monomer, either by expressing a nuclear localised active mutant of the actin polymerising protein mDIA, silencing components of the nuclear actin import complex IPO9 and CFL1 or overexpressing the nuclear export complex XPO6, rescued RelA/p65 levels and NF-κB reporter gene activity in forskolin-stimulated cells. Elevated cAMP or NLS-Actin_R62D reduced the half-life of RelA/p65, which was reversed by the proteasome inhibitor MG132. Accordingly, forskolin stimulated association of RelA/p65 with ubiquitin affinity beads, indicating increased ubiquitination of RelA/p65 or associated proteins. Taken together, our data demonstrate a novel mechanism underlying the anti-inflammatory effects of cAMP and highlight the important role played by nuclear actin in the regulation of inflammation. Full article

(This article belongs to the Special Issue Cyclic AMP/PKA/Epac Signaling in Health and Disease)

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19 pages, 3716 KiB

Open AccessArticle

Preconditioning or Postconditioning with 8-Br-cAMP-AM Protects the Heart against Regional Ischemia and Reperfusion: A Role for Mitochondrial Permeability Transition

by Igor Khaliulin, Raimondo Ascione, Leonid N. Maslov, Haitham Amal and M. Saadeh Suleiman

Cells 2021, 10(5), 1223; https://doi.org/10.3390/cells10051223 - 17 May 2021

Cited by 11 | Viewed by 3201

Abstract

The cAMP analogue 8-Br-cAMP-AM (8-Br) confers marked protection against global ischaemia/reperfusion of isolated perfused heart. We tested the hypothesis that 8-Br is also protective under clinically relevant conditions (regional ischaemia) when applied either before ischemia or at the beginning of reperfusion, and this effect is associated with the mitochondrial permeability transition pore (MPTP). 8-Br (10 μM) was administered to Langendorff-perfused rat hearts for 5 min either before or at the end of 30 min regional ischaemia. Ca²⁺-induced mitochondria swelling (a measure of MPTP opening) and binding of hexokinase II (HKII) to mitochondria were assessed following the drug treatment at preischaemia. Haemodynamic function and ventricular arrhythmias were monitored during ischaemia and 2 h reperfusion. Infarct size was evaluated at the end of reperfusion. 8-Br administered before ischaemia attenuated ventricular arrhythmias, improved haemodynamic function, and reduced infarct size during ischaemia/reperfusion. Application of 8-Br at the end of ischaemia protected the heart during reperfusion. 8-Br promoted binding of HKII to the mitochondria and reduced Ca²⁺-induced mitochondria swelling. Thus, 8-Br protects the heart when administered before regional ischaemia or at the beginning of reperfusion. This effect is associated with inhibition of MPTP via binding of HKII to mitochondria, which may underlie the protective mechanism. Full article

(This article belongs to the Special Issue Cyclic AMP/PKA/Epac Signaling in Health and Disease)

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Review

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21 pages, 1989 KiB

Open AccessReview

cAMP-Dependent Signaling and Ovarian Cancer

by Agnieszka Kilanowska, Agnieszka Ziółkowska, Piotr Stasiak and Magdalena Gibas-Dorna

Cells 2022, 11(23), 3835; https://doi.org/10.3390/cells11233835 - 29 Nov 2022

Cited by 7 | Viewed by 5441

Abstract

cAMP-dependent pathway is one of the most significant signaling cascades in healthy and neoplastic ovarian cells. Working through its major effector proteins—PKA and EPAC—it regulates gene expression and many cellular functions. PKA promotes the phosphorylation of cAMP response element-binding protein (CREB) which mediates gene transcription, cell migration, mitochondrial homeostasis, cell proliferation, and death. EPAC, on the other hand, is involved in cell adhesion, binding, differentiation, and interaction between cell junctions. Ovarian cancer growth and metabolism largely depend on changes in the signal processing of the cAMP-PKA-CREB axis, often associated with neoplastic transformation, metastasis, proliferation, and inhibition of apoptosis. In addition, the intracellular level of cAMP also determines the course of other pathways including AKT, ERK, MAPK, and mTOR, that are hypo- or hyperactivated among patients with ovarian neoplasm. With this review, we summarize the current findings on cAMP signaling in the ovary and its association with carcinogenesis, multiplication, metastasis, and survival of cancer cells. Additionally, we indicate that targeting particular stages of cAMP-dependent processes might provide promising therapeutic opportunities for the effective management of patients with ovarian cancer. Full article

(This article belongs to the Special Issue Cyclic AMP/PKA/Epac Signaling in Health and Disease)

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32 pages, 3151 KiB

Open AccessReview

cAMP Signaling in Cancer: A PKA-CREB and EPAC-Centric Approach

by Muhammad Bilal Ahmed, Abdullah A. A. Alghamdi, Salman Ul Islam, Joon-Seok Lee and Young-Sup Lee

Cells 2022, 11(13), 2020; https://doi.org/10.3390/cells11132020 - 24 Jun 2022

Cited by 37 | Viewed by 8379

Abstract

Cancer is one of the most common causes of death globally. Despite extensive research and considerable advances in cancer therapy, the fundamentals of the disease remain unclear. Understanding the key signaling mechanisms that cause cancer cell malignancy may help to uncover new pharmaco-targets. Cyclic adenosine monophosphate (cAMP) regulates various biological functions, including those in malignant cells. Understanding intracellular second messenger pathways is crucial for identifying downstream proteins involved in cancer growth and development. cAMP regulates cell signaling and a variety of physiological and pathological activities. There may be an impact on gene transcription from protein kinase A (PKA) as well as its downstream effectors, such as cAMP response element-binding protein (CREB). The position of CREB downstream of numerous growth signaling pathways implies its oncogenic potential in tumor cells. Tumor growth is associated with increased CREB expression and activation. PKA can be used as both an onco-drug target and a biomarker to find, identify, and stage tumors. Exploring cAMP effectors and their downstream pathways in cancer has become easier using exchange protein directly activated by cAMP (EPAC) modulators. This signaling system may inhibit or accelerate tumor growth depending on the tumor and its environment. As cAMP and its effectors are critical for cancer development, targeting them may be a useful cancer treatment strategy. Moreover, by reviewing the material from a distinct viewpoint, this review aims to give a knowledge of the impact of the cAMP signaling pathway and the related effectors on cancer incidence and development. These innovative insights seek to encourage the development of novel treatment techniques and new approaches. Full article

(This article belongs to the Special Issue Cyclic AMP/PKA/Epac Signaling in Health and Disease)

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