cGMP Signaling in the Cardiovascular System—The Role of Compartmentation and Its Live Cell Imaging

Bork, Nadja I.; Nikolaev, Viacheslav O.

doi:10.3390/ijms19030801

Cited by 22 publications

(14 citation statements)

References 125 publications

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“…It has been previously reported that specificity of PKG signaling in cardiomyocytes is maintained via the involvement of pGC versus sGC (14). Consistent with this notion, our study demonstrated separate patterns of RyR2 PKG phosphorylation via ANPR and M2R, globally versus locally, respectively.…”

Section: Discussionsupporting

confidence: 91%

“…It has been previously reported that specificity of PKG signaling in cardiomyocytes is maintained via the involvement of receptormediated particulate guanylate cyclase (pGC) and soluble guanylate cyclase (sGC) (13). In addition, there is evidence of cyclic guanylate monophosphate (cGMP) compartmentalization in cardiomyocytes whereby b3AR-eNOS-NO-sGC-NO-PKG(b 3 -adrenergicreceptor-endothelialnitricoxidesynthasenitric oxide-sGC-cGMP-PKG) signaling occurs separately from a pGC-cGMP pool mediated via atrial natriuretic peptide receptor (ANPR)-pGC-cGMP-PKG signaling (14). Although extensively characterized in other cell types (15,16), the specific molecular events linking muscarinic stimulation and cGMP-PKG-dependent phosphorylation of target effectors, including components of Ca handling, remain to be elucidated in cardiomyocytes.…”

mentioning

confidence: 99%

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Muscarinic-dependent phosphorylation of the cardiac ryanodine receptor by protein kinase G is mediated by PI3K–AKT–nNOS signaling

Baine¹,

Thomas²,

Bonilla³

et al. 2020

Journal of Biological Chemistry

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Post-translational modifications of proteins involved in calcium handling in myocytes, such as the cardiac ryanodine receptor (RyR2), critically regulate cardiac contractility. Recent studies have suggested that phosphorylation of RyR2 by protein kinase G (PKG) might contribute to the cardioprotective effects of cholinergic stimulation. However, the specific mechanisms underlying these effects remain unclear. Here, using murine ventricular myocytes, immunoblotting, proximity ligation assays, and nitric oxide imaging, we report that phosphorylation of Ser-2808 in RyR2 induced by the muscarinic receptor agonist carbachol (CCh) is mediated by a signaling axis comprising phosphoinositide 3-phosphate kinase (PI3K), AKT Ser/Thr kinase (AKT), nitric oxide synthase 1 (NOS1 or nNOS), nitric oxide (NO), soluble guanylate cyclase (sGC), cGMP, and PKG. We found that this signaling pathway is compartmentalized in myocytes, as it was distinct from atrial natriuretic peptide receptor (ANPR)–cGMP–PKG–RyR2 Ser-2808 signaling and independent of muscarinic-induced phosphorylation of Ser-239 in vasodilator-stimulated phosphoprotein (VASP). These results provide detailed insights into muscarinic-induced PKG signaling and the mediators that regulate cardiac RyR2 phosphorylation critical for cardiovascular function.

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

Muscarinic-dependent phosphorylation of the cardiac ryanodine receptor by protein kinase G is mediated by PI3K–AKT–nNOS signaling

Baine¹,

Thomas²,

Bonilla³

et al. 2020

Journal of Biological Chemistry

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“…cGi500 has an EC 50 for cGMP of 500 µM (Russwurm et al, 2007), which is probably not optimized to detection of cGMP concentrations induced by neurohormonal stimuli. Another cGMP biosensor, redcGES-DE5, has an EC 50 of ∼40 nM (Nikolaev et al, 2006; Bork and Nikolaev, 2018) and could be used to detect small changes in cGMP concentration that are often present in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Illuminating cell signaling with genetically encoded FRET biosensors in adult mouse cardiomyocytes

Reddy

West

Jian

et al. 2018

Journal of General Physiology

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FRET-based biosensor experiments in adult cardiomyocytes are a powerful way of dissecting the spatiotemporal dynamics of the complicated signaling networks that regulate cardiac health and disease. However, although much information has been gleaned from FRET studies on cardiomyocytes from larger species, experiments on adult cardiomyocytes from mice have been difficult at best. Thus the large variety of genetic mouse models cannot be easily used for this type of study. Here we develop cell culture conditions for adult mouse cardiomyocytes that permit robust expression of adenoviral FRET biosensors and reproducible FRET experimentation. We find that addition of 6.25 µM blebbistatin or 20 µM (S)-nitro-blebbistatin to a minimal essential medium containing 10 mM HEPES and 0.2% BSA maintains morphology of cardiomyocytes from physiological, pathological, and transgenic mouse models for up to 50 h after adenoviral infection. This provides a 10–15-h time window to perform reproducible FRET readings using a variety of CFP/YFP sensors between 30 and 50 h postinfection. The culture is applicable to cardiomyocytes isolated from transgenic mouse models as well as models with cardiac diseases. Therefore, this study helps scientists to disentangle complicated signaling networks important in health and disease of cardiomyocytes.

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“…[88]. Имеющиеся данные свидетельствуют о том, что молекулы цГМФ, образующиеся при стимуляции рГЦ и мГЦ, разобщены в пространстве внутри клеток, вследствие чего имеют отличающиеся функции, несмот ря на структурную идентичность [24,89]. Более того, при СН имеются риски развития резистентности миокарда и сосудов к BNP за счет снижения активности самих молекул или их рецепторов на клеточном уровне, а также инактивации при воздействии клеточных протеиназ [90].…”

Section: натрийуретические пептиды и неприлизинunclassified

Nitric oxide — soluble guanylate cyclase — cyclic guanosine monophosphate signaling pathway in the pathogenesis of heart failure and search for novel therapeutic targets

Кобалава

Лазарев

2021

Cardiovasc Ther Prev

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Heart failure is a severe disease with an unfavorable prognosis, which requires intensification of therapy and the search for novel approaches to treatment. In this review, the physiological significance of soluble guanylate cyclase-related signaling pathway, reasons for decrease in its activity in heart failure and possible consequences are discussed. Pharmacological methods of stimulating the production of cyclic guanosine monophosphate using drugs with different mechanisms of action are considered. Data from clinical studies regarding their effectiveness and safety are presented. A promising approach is stimulation of soluble guanylate cyclase, which showed beneficial effects in preclinical studies, as well as in the recently completed phase III VICTORIA study.

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cGMP Signaling in the Cardiovascular System—The Role of Compartmentation and Its Live Cell Imaging

Cited by 22 publications

References 125 publications

Muscarinic-dependent phosphorylation of the cardiac ryanodine receptor by protein kinase G is mediated by PI3K–AKT–nNOS signaling

Muscarinic-dependent phosphorylation of the cardiac ryanodine receptor by protein kinase G is mediated by PI3K–AKT–nNOS signaling

Illuminating cell signaling with genetically encoded FRET biosensors in adult mouse cardiomyocytes

Nitric oxide — soluble guanylate cyclase — cyclic guanosine monophosphate signaling pathway in the pathogenesis of heart failure and search for novel therapeutic targets

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