Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling

Reinhardt, Franziska; Beneke, Kira; Pavlidou, Nefeli Grammatica; Conradi, Lenard; Reichenspurner, Hermann; Hove‐Madsen, Leif; Molina, Cristina E.

doi:10.3390/cells10113042

Cited by 20 publications

(19 citation statements)

References 68 publications

(121 reference statements)

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“…Cardiomyocyte and tissue responses to stressors are mediated by an intricate signaling network that allows the heart to adapt and meet physiological needs. Among these signals, protein kinase A (PKA) and Ca 2+/ calmodulin-dependent protein kinase II (CaMKII) are two protein kinases that phosphorylate a vast array of ion channels and Ca 2+ -handling and regulatory proteins, and play critical roles in fine-tuning atrial cardiomyocyte stress responses (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). These involve changes in transmembrane potential homeostasis via both direct influences on sarcolemmal ion channels and transporters, as well as indirect changes in Ca 2+ signaling that acutely regulate transmembrane fluxes and can lead to remodeling in the chronic (pathologic) setting (14, 19, 21-24, 26, 28).…”

Section: Introductionmentioning

confidence: 99%

Integrative human atrial modeling unravels interactive PKA and CaMKII signaling as key determinant of atrial arrhythmogenesis

Ni¹,

Morotti²,

Zhang³

et al. 2022

Preprint

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Atrial fibrillation (AF), the most prevalent clinical arrhythmia, is associated with atrial remodeling manifesting as acute and chronic alterations in expression, function, and regulation of atrial electrophysiological and Ca2+-handling processes. These AF-induced modifications crosstalk and propagate across spatial scales creating a complex pathophysiological network, which renders AF resistant to existing pharmacotherapies that predominantly target transmembrane ion channels. Developing innovative therapeutic strategies requires a systems approach to disentangle quantitatively the proarrhythmic contributions of individual AF-induced alterations. Here, we built a novel computational framework for simulating electrophysiology and Ca2+-handling in human atrial cardiomyocytes and tissues, and their regulation by key upstream signaling pathways (i.e., protein kinase A, PKA, and Ca2+/calmodulin-dependent protein kinase II, CaMKII) involved in AF-pathogenesis. Populations of atrial cardiomyocyte models were constructed to determine the influence of subcellular ionic processes, signaling components, and regulatory networks on atrial arrhythmogenesis. Our results reveal a novel synergistic crosstalk between PKA and CaMKII that promotes atrial cardiomyocyte electrical instability and arrhythmogenic triggered activity. Simulations of heterogeneous tissue demonstrate that this cellular triggered activity is further amplified by CaMKII-dependent alterations of tissue properties, further exacerbating atrial arrhythmogenesis. Our analysis positions CaMKII as a key nodal master switch of the adaptive changes and the maladaptive proarrhythmic triggers at the cellular and tissue levels and establishes CaMKII inhibition as potential anti-AF strategy. Collectively, our integrative approach is powerful and instrumental to assemble and reconcile existing knowledge into a systems network for identifying novel anti-AF targets and innovative approaches moving beyond the traditional ion channel-based strategy.Significance statementDespite significant advancement in our understanding of pathological mechanisms and alterations underlying atrial fibrillation (AF), a highly prevalent clinical arrhythmia causing substantial health and socioeconomic burden, development of effective pharmacological therapeutics for AF remains an urgent unmet clinical need. We built a systems framework integrating key processes and their regulatory upstream signaling pathways that are involved in atrial electrophysiology and modified by AF. By simulating populations of single atrial cardiomyocyte models and heterogeneous tissues, our analysis demonstrated synergistic interactions between upstream signaling pathways that promote atrial arrhythmogenesis across spatial scales, added new insight into complex atrial arrhythmia mechanisms, and revealed adaptive and maladaptive alterations caused by AF, thus providing a powerful new tool for identifying innovative therapeutic approaches against AF.

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Section: Introductionmentioning

confidence: 99%

Integrative human atrial modeling unravels interactive PKA and CaMKII signaling as key determinant of atrial arrhythmogenesis

Ni¹,

Morotti²,

Zhang³

et al. 2022

Preprint

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Section: Discussionmentioning

confidence: 99%

“…The activation of β adrenergic receptors in heart cells stimulates Ca 2+ release by increasing the activity of SERCA pumps without any evidence of an overloaded SR Ca 2+ pool (Zhou et al, 1999;Maxwell and Blatter, 2012). This occurs because there is a compensatory higher RyR2 leak activity (Reinhardt et al, 2021;Nolla-Colomer et al, 2022) The evidence indicates that translocon presents significant participation in the ER Ca 2+ leak in pancreatic acinar cells (Lomax et al, 2002), human salivary glands (Ong et al, 2007), liver microsomes from rats (Giunti et al, 2007), andLNCaP cells (van Coppenolle et al, 2004), suggesting that Ca 2+ leak activity of Sec61α has a critical role in establishing the steady-state ER Ca 2+ level. However, translocon does not seem to be operating as an SR Ca 2+ leak channel under basal conditions in smooth muscle cells.…”

Section: Role Of Serca Pump Activity In the Facilitation Of Ca 2+ Rel...mentioning

confidence: 99%

PKC Inhibits Sec61 Translocon-Mediated Sarcoplasmic Reticulum Ca2+ Leak in Smooth Muscle Cells

Dagnino-Acosta

Guerrero‐Hernández²

2022

Front. Physiol.

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PKC inhibitors stimulate Ca2+ release from internal stores in diverse cell types. Our data indicate that this action cannot be explained by an increased agonist-induced IP3 production or an overloaded SR Ca2+ pool in smooth muscle cells from guinea pig urinary bladder. The incubation of these cells with three different PKC inhibitors, such as Go6976, Go6983, and BIM 1, resulted in a higher SR Ca2+ leak revealed by inhibition of the SERCA pump with thapsigargin. This SR Ca2+ leakage was sensitive to protein translocation inhibitors such as emetine and anisomycin. Since this increased SR Ca2+ leak did not result in a depleted SR Ca2+ store, we have inferred there was a compensatory increase in SERCA pump activity, resulting in a higher steady-state. This new steady-state increased the frequency of Spontaneous Transient Outward Currents (STOCs), which reflect the activation of high conductance, Ca2+-sensitive potassium channels in response to RyR-mediated Ca2+ sparks. This increased STOC frequency triggered by PKC inhibition was restored to normal by inhibiting translocon-mediated Ca2+ leak with emetine. These results suggest a critical role of PKC-mediated translocon phosphorylation in regulating SR Ca2+ steady-state, which, in turn, alters SR Ca2+ releasing activity.

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“…Consequently, the cytosolic Ca 2+ overload activates the Na + -Ca 2+ antiporter (NCX) to remove Ca 2+ from cells with a stoichiometry of 3Na + :1Ca 2+ [ 108 ]. The associated inward NCX current (I NCX ) can induce delayed afterdepolarizations (DADs) [ 109 ], which can be sufficient to meet the threshold cell membrane voltage and to trigger an action potential [ 110 ].…”

Section: Pathophysiology Of Atrial Fibrillationmentioning

confidence: 99%

“…In atrial cardiomyocytes, a reduced L-type Ca2 + current (ICa,L) density [ 154 ] and increased spontaneous Ca 2+ release from the sarcoplasmic reticulum through the ryanodine receptor [ 110 ] are implicated in the cytosolic Ca 2+ overload responsible for delayed afterdepolarization (DAD), which promotes AF [ 116 , 117 ]. These effects on calcium remodeling are consistent with adenosine receptor signaling.…”

Section: Arrhythmogenic Effects Of the Adenosinergic Systemmentioning

confidence: 99%

Adenosine and Adenosine Receptors: Advances in Atrial Fibrillation

et al. 2022

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Atrial fibrillation (AF) is the most common arrhythmia in the world. Because the key to developing innovative therapies that limit the onset and the progression of AF is to fully understand the underlying molecular mechanisms of AF, the aim of the present narrative review is to report the most recent advances in the potential role of the adenosinergic system in the pathophysiology of AF. After a comprehensive approach describing adenosinergic system signaling and the mechanisms of the initiation and maintenance of AF, we address the interactions of the adenosinergic system’s signaling with AF. Indeed, adenosine release can activate four G-coupled membrane receptors, named A1, A2A, A2B and A3. Activation of the A2A receptors can promote the occurrence of delayed depolarization, while activation of the A1 receptors can shorten the action potential’s duration and induce the resting membrane’s potential hyperpolarization, which promote pulmonary vein firing, stabilize the AF rotors and allow for functional reentry. Moreover, the A2B receptors have been associated with atrial fibrosis homeostasis. Finally, the adenosinergic system can modulate the autonomous nervous system and is associated with AF risk factors. A question remains regarding adenosine release and the adenosine receptors’ activation and whether this would be a cause or consequence of AF.

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Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling

Cited by 20 publications

References 68 publications

Integrative human atrial modeling unravels interactive PKA and CaMKII signaling as key determinant of atrial arrhythmogenesis

Integrative human atrial modeling unravels interactive PKA and CaMKII signaling as key determinant of atrial arrhythmogenesis

PKC Inhibits Sec61 Translocon-Mediated Sarcoplasmic Reticulum Ca2+ Leak in Smooth Muscle Cells

Adenosine and Adenosine Receptors: Advances in Atrial Fibrillation

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