Abnormal Calcium Handling in Atrial Fibrillation Is Linked to Changes in Cyclic AMP Dependent Signaling
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 r...
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| Autores principales: | , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/8d9f6f41600e43bab75a43f1a64a42a4 |
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| Sumario: | 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). |
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