mAKAPβ signalosomes – A nodal regulator of gene transcription associated with pathological cardiac remodeling

Dodge‐Kafka, Kimberly L.; Gildart, Moriah; Tokarski, Kristin; Kapiloff, Michael S.

doi:10.1016/j.cellsig.2019.109357

Cited by 24 publications

(31 citation statements)

References 89 publications

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“…As perhaps expected, given its perinuclear localization, the signalosome organized by mAKAPb is involved in the modulation of transcriptional regulation (Dodge-Kafka et al, 2019). In cardiac myocytes, the mAKAPb signalosome has been proposed to nucleate the effect of distinct pools of cAMP, which either activate or block transcription of pro-hypertrophic genes Zhang and Eggert, 2013;Kritzer et al, 2014).…”

Section: G Nucleusmentioning

confidence: 83%

Subcellular Organization of the cAMP Signaling Pathway

2020

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Section: G Nucleusmentioning

confidence: 83%

Subcellular Organization of the cAMP Signaling Pathway

2020

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“…In the heart, AKAPs have been shown to regulate multiple physiological responses including cardiac contraction, rhythm and energy production as well as pathological functions linked to the development of arrhythmias, cardiac hypertrophy, fibrosis, and heart failure [7,141,142]. Several studies indicate that altering AKAP expression and signaling in cardiomyocytes can significantly impact their ability to survive cardiac stress and consequently influence replacement fibrosis [33,140,[143][144][145]. Since these results have been extensively reviewed in recent years, in the next paragraphs we will mainly focus on recent findings highlighting the role of AKAP signaling in cardiac fibroblasts.…”

Section: A-kinase Anchoring Proteinsmentioning

confidence: 99%

The Role of Cyclic AMP Signaling in Cardiac Fibrosis

Delaunay

Osman

Kaiser

et al. 2019

Cells

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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.

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“…Provocatively, while AC1/8 double knock-out reduced KCl-dependent cyclase activity in hippocampal neurons ∼60%, KCl could also activate AC in these cells via activation of calcineurin ( Chan et al, 2005 ). As mAKAPβ binds active calcineurin promoting the dephosphorylation of NFATc and MEF2 transcription factors ( Dodge-Kafka et al, 2019 ), it is possible that KCl and Ca 2+ activates AC in the mAKAPα compartment via a calcineurin-dependent pathway. The identification of the AC(s) critical for perinuclear cAMP-dependent neurite extension and neuroprotection will require future studies involving specific interference with the expression (RNAi) of individual cyclases and PN-AKAR4 imaging.…”

Section: Discussionmentioning

confidence: 99%

“…Expressed in neurons and striated myocytes, the large 250-kDa mAKAP (AKAP6) scaffold (α-isoform in neurons, β-isoform in myocytes) is localized to the nuclear envelope via binding to the Klarsicht/ANC-1/Syne-1 homology (KASH) domain, transmembrane protein nesprin-1α ( Pare et al, 2005a ; Boczek et al, 2019 ). mAKAP binds >20 different signaling enzymes and gene regulatory proteins, thereby regulating stress-induced gene expression in these excitable cells ( Dodge-Kafka et al, 2019 ). mAKAP was the first AKAP to be shown to be capable of binding an adenylyl cyclase (AC), a phosphodiesterase (PDE), and a cAMP effector, thus having the potential to orchestrate completely compartmentalized cAMP signaling ( Dodge et al, 2001 ; Dodge-Kafka et al, 2005 ; Kapiloff et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

cAMP at Perinuclear mAKAPα Signalosomes Is Regulated by Local Ca²⁺ Signaling in Primary Hippocampal Neurons

Boczek

Zhu³

et al. 2021

eNeuro

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The second messenger cyclic adenosine monophosphate (cAMP) is important for the regulation of neuronal structure and function, including neurite extension. A perinuclear cAMP compartment organized by the scaffold protein muscle A-kinase anchoring protein α (mAKAPα/AKAP6α) is sufficient and necessary for axon growth by rat hippocampal neurons in vitro . Here, we report that cAMP at mAKAPα signalosomes is regulated by local Ca 2+ signaling that mediates activity-dependent cAMP elevation within that compartment. Simultaneous Forster resonance energy transfer (FRET) imaging using the protein kinase A (PKA) activity reporter AKAR4 and intensiometric imaging using the RCaMP1h fluorescent Ca 2+ sensor revealed that membrane depolarization by KCl selectively induced activation of perinuclear PKA activity. Activity-dependent perinuclear PKA activity was dependent on expression of the mAKAPα scaffold, while both perinuclear Ca 2+ elevation and PKA activation were dependent on voltage-dependent L-type Ca 2+ channel activity. Importantly, chelation of Ca 2+ by a nuclear envelope-localized parvalbumin fusion protein inhibited both activity-induced perinuclear PKA activity and axon elongation. Together, this study provides evidence for a model in which a neuronal perinuclear cAMP compartment is locally regulated by activity-dependent Ca 2+ influx, providing local control for the enhancement of neurite extension.

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mAKAPβ signalosomes – A nodal regulator of gene transcription associated with pathological cardiac remodeling

Cited by 24 publications

References 89 publications

Subcellular Organization of the cAMP Signaling Pathway

Subcellular Organization of the cAMP Signaling Pathway

The Role of Cyclic AMP Signaling in Cardiac Fibrosis

cAMP at Perinuclear mAKAPα Signalosomes Is Regulated by Local Ca²⁺ Signaling in Primary Hippocampal Neurons

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mAKAPβ signalosomes – A nodal regulator of gene transcription associated with pathological cardiac remodeling

Cited by 24 publications

References 89 publications

Subcellular Organization of the cAMP Signaling Pathway

Subcellular Organization of the cAMP Signaling Pathway

The Role of Cyclic AMP Signaling in Cardiac Fibrosis

cAMP at Perinuclear mAKAPα Signalosomes Is Regulated by Local Ca2+ Signaling in Primary Hippocampal Neurons

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Product

Resources

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cAMP at Perinuclear mAKAPα Signalosomes Is Regulated by Local Ca²⁺ Signaling in Primary Hippocampal Neurons