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

Both, the decreased L-type Ca2+ current (ICa,L) density and increased spontaneous Ca2+ release from the sarcoplasmic reticulum (SR), have been associated with atrial fibrillation (AF). In this study, we tested the hypothesis that r...

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Autores principales:	Franziska Reinhardt, Kira Beneke, Nefeli Grammatica Pavlidou, Lenard Conradi, Hermann Reichenspurner, Leif Hove-Madsen, Cristina E. Molina
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	atrial fibrillation (AF) cAMP-dependent regulation protein kinase A (PKA) L-type calcium current (I<sub>Ca,L</sub>) transient inward current (I<sub>TI</sub>) patch-clamp Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/8d9f6f41600e43bab75a43f1a64a42a4
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spelling	oai:doaj.org-article:8d9f6f41600e43bab75a43f1a64a42a42021-11-25T17:10:42ZAbnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling10.3390/cells101130422073-4409https://doaj.org/article/8d9f6f41600e43bab75a43f1a64a42a42021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3042https://doaj.org/toc/2073-4409Both, the decreased L-type Ca<sup>2+</sup> current (I<sub>Ca,L</sub>) density and increased spontaneous Ca<sup>2+</sup> release from the sarcoplasmic reticulum (SR), have been associated with atrial fibrillation (AF). In this study, we tested the hypothesis that remodeling of 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) signaling is linked to these compartment-specific changes (up- or down-regulation) in Ca<sup>2+</sup>-handling. Perforated patch-clamp experiments were performed in atrial myocytes from 53 patients with AF and 104 patients in sinus rhythm (Ctl). A significantly higher frequency of transient inward currents (I<sub>TI</sub>) activated by spontaneous Ca<sup>2+</sup> release was confirmed in myocytes from AF patients. Next, inhibition of PKA by H-89 promoted a stronger effect on the I<sub>TI</sub> frequency in these myocytes compared to myocytes from Ctl patients (7.6-fold vs. 2.5-fold reduction), while the β-agonist isoproterenol (ISO) caused a greater increase in Ctl patients (5.5-fold vs. 2.1-fold). I<sub>Ca,L</sub> density was larger in myocytes from Ctl patients at baseline (<i>p</i> < 0.05). However, the effect of ISO on I<sub>Ca,L</sub> density was only slightly stronger in AF than in Ctl myocytes (3.6-fold vs. 2.7-fold). Interestingly, a significant reduction of I<sub>Ca,L</sub> and Ca<sup>2+</sup> sparks was observed upon Ca<sup>2+</sup>/Calmodulin-dependent protein kinase II inhibition by KN-93, but this inhibition had no effect on I<sub>TI</sub>. Fluorescence resonance energy transfer (FRET) experiments showed that although AF promoted cytosolic desensitization to β-adrenergic stimulation, ISO increased cAMP to similar levels in both groups of patients in the L-type Ca<sup>2+</sup> channel and ryanodine receptor compartments. Basal cAMP signaling also showed compartment-specific regulation by phosphodiesterases in atrial myocytes from 44 Ctl and 43 AF patients. Our results suggest that AF is associated with opposite changes in compartmentalized PKA/cAMP-dependent regulation of I<sub>Ca,L</sub> (down-regulation) and I<sub>TI</sub> (up-regulation).Franziska ReinhardtKira BenekeNefeli Grammatica PavlidouLenard ConradiHermann ReichenspurnerLeif Hove-MadsenCristina E. MolinaMDPI AGarticleatrial fibrillation (AF)cAMP-dependent regulationprotein kinase A (PKA)L-type calcium current (I<sub>Ca,L</sub>)transient inward current (I<sub>TI</sub>)patch-clampBiology (General)QH301-705.5ENCells, Vol 10, Iss 3042, p 3042 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	atrial fibrillation (AF) cAMP-dependent regulation protein kinase A (PKA) L-type calcium current (I<sub>Ca,L</sub>) transient inward current (I<sub>TI</sub>) patch-clamp Biology (General) QH301-705.5
spellingShingle	atrial fibrillation (AF) cAMP-dependent regulation protein kinase A (PKA) L-type calcium current (I<sub>Ca,L</sub>) transient inward current (I<sub>TI</sub>) patch-clamp Biology (General) QH301-705.5 Franziska Reinhardt Kira Beneke Nefeli Grammatica Pavlidou Lenard Conradi Hermann Reichenspurner Leif Hove-Madsen Cristina E. Molina Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling
description	Both, the decreased L-type Ca<sup>2+</sup> current (I<sub>Ca,L</sub>) density and increased spontaneous Ca<sup>2+</sup> release from the sarcoplasmic reticulum (SR), have been associated with atrial fibrillation (AF). In this study, we tested the hypothesis that remodeling of 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) signaling is linked to these compartment-specific changes (up- or down-regulation) in Ca<sup>2+</sup>-handling. Perforated patch-clamp experiments were performed in atrial myocytes from 53 patients with AF and 104 patients in sinus rhythm (Ctl). A significantly higher frequency of transient inward currents (I<sub>TI</sub>) activated by spontaneous Ca<sup>2+</sup> release was confirmed in myocytes from AF patients. Next, inhibition of PKA by H-89 promoted a stronger effect on the I<sub>TI</sub> frequency in these myocytes compared to myocytes from Ctl patients (7.6-fold vs. 2.5-fold reduction), while the β-agonist isoproterenol (ISO) caused a greater increase in Ctl patients (5.5-fold vs. 2.1-fold). I<sub>Ca,L</sub> density was larger in myocytes from Ctl patients at baseline (<i>p</i> < 0.05). However, the effect of ISO on I<sub>Ca,L</sub> density was only slightly stronger in AF than in Ctl myocytes (3.6-fold vs. 2.7-fold). Interestingly, a significant reduction of I<sub>Ca,L</sub> and Ca<sup>2+</sup> sparks was observed upon Ca<sup>2+</sup>/Calmodulin-dependent protein kinase II inhibition by KN-93, but this inhibition had no effect on I<sub>TI</sub>. Fluorescence resonance energy transfer (FRET) experiments showed that although AF promoted cytosolic desensitization to β-adrenergic stimulation, ISO increased cAMP to similar levels in both groups of patients in the L-type Ca<sup>2+</sup> channel and ryanodine receptor compartments. Basal cAMP signaling also showed compartment-specific regulation by phosphodiesterases in atrial myocytes from 44 Ctl and 43 AF patients. Our results suggest that AF is associated with opposite changes in compartmentalized PKA/cAMP-dependent regulation of I<sub>Ca,L</sub> (down-regulation) and I<sub>TI</sub> (up-regulation).
format	article
author	Franziska Reinhardt Kira Beneke Nefeli Grammatica Pavlidou Lenard Conradi Hermann Reichenspurner Leif Hove-Madsen Cristina E. Molina
author_facet	Franziska Reinhardt Kira Beneke Nefeli Grammatica Pavlidou Lenard Conradi Hermann Reichenspurner Leif Hove-Madsen Cristina E. Molina
author_sort	Franziska Reinhardt
title	Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling
title_short	Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling
title_full	Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling
title_fullStr	Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling
title_full_unstemmed	Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling
title_sort	abnormal calcium handling in atrial fibrillation is linked to changes in cyclic amp dependent signaling
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/8d9f6f41600e43bab75a43f1a64a42a4
work_keys_str_mv	AT franziskareinhardt abnormalcalciumhandlinginatrialfibrillationislinkedtochangesincyclicampdependentsignaling AT kirabeneke abnormalcalciumhandlinginatrialfibrillationislinkedtochangesincyclicampdependentsignaling AT nefeligrammaticapavlidou abnormalcalciumhandlinginatrialfibrillationislinkedtochangesincyclicampdependentsignaling AT lenardconradi abnormalcalciumhandlinginatrialfibrillationislinkedtochangesincyclicampdependentsignaling AT hermannreichenspurner abnormalcalciumhandlinginatrialfibrillationislinkedtochangesincyclicampdependentsignaling AT leifhovemadsen abnormalcalciumhandlinginatrialfibrillationislinkedtochangesincyclicampdependentsignaling AT cristinaemolina abnormalcalciumhandlinginatrialfibrillationislinkedtochangesincyclicampdependentsignaling
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Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling

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