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Calmodulin kinase II regulates atrial myocyte late sodium current, calcium handling, and atrial arrhythmia.

ABSTRACT: BACKGROUND:Atrial fibrillation (AF) is the most common type of arrhythmia. Abnormal atrial myocyte Ca2+ handling promotes aberrant membrane excitability and remodeling that are important for atrial arrhythmogenesis. The sequence of molecular events leading to loss of normal atrial myocyte Ca2+ homeostasis is not established. Late Na+ current (INa,L) is increased in atrial myocytes from AF patients together with an increase in activity of Ca2+/calmodulin-dependent kinase II (CaMKII). OBJECTIVE:The purpose of this study was to determine whether CaMKII-dependent phosphorylation at Ser571 on NaV1.5 increases atrial INa,L, leading to aberrant atrial Ca2+ cycling, altered electrophysiology, and increased AF risk. METHODS:Atrial myocyte electrophysiology, Ca2+ handling, and arrhythmia susceptibility were studied in wild-type and Scn5a knock-in mice expressing phosphomimetic (S571E) or phosphoresistant (S571A) NaV1.5 at Ser571. RESULTS:Atrial myocytes from S571E but not S571A mice displayed an increase in INa,L and action potential duration, and with adrenergic stress have increased delayed afterdepolarizations. Frequency of Ca2+ sparks and waves was increased in S571E atrial myocytes compared to wild type. S571E mice showed an increase in atrial events induced by adrenergic stress and AF inducibility in vivo. Isolated S571E atria were more susceptible to spontaneous atrial events, which were abrogated by inhibiting sarcoplasmic reticulum Ca2+ release, CaMKII, or the Na+/Ca2+ exchanger. Expression of phospho-NaV1.5 at Ser571 and autophosphorylated CaMKII were increased in atrial samples from human AF patients. CONCLUSION:This study identified CaMKII-dependent regulation of NaV1.5 as an important upstream event in Ca2+ handling defects and abnormal impulse generation in the setting of AF.

SUBMITTER: Greer-Short A

PROVIDER: S-EPMC7056561 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Calmodulin kinase II regulates atrial myocyte late sodium current, calcium handling, and atrial arrhythmia.

Greer-Short Amara A Musa Hassan H Alsina Katherina M KM Ni Li L Word Tarah A TA Reynolds Julia O JO Gratz Daniel D Lane Cemantha C El-Refaey Mona M Unudurthi Sathya S Skaf Michel M Li Ning N Fedorov Vadim V VV Wehrens Xander H T XHT Mohler Peter J PJ Hund Thomas J TJ

Heart rhythm 20191014 3

<h4>Background</h4>Atrial fibrillation (AF) is the most common type of arrhythmia. Abnormal atrial myocyte Ca<sup>2+</sup> handling promotes aberrant membrane excitability and remodeling that are important for atrial arrhythmogenesis. The sequence of molecular events leading to loss of normal atrial myocyte Ca<sup>2+</sup> homeostasis is not established. Late Na<sup>+</sup> current (I<sub>Na,L</sub>) is increased in atrial myocytes from AF patients together with an increase in activity of Ca<sup ...[more]

PMID: 31622781

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Project description:Slowly inactivating Na+ channels conducting "late" Na+ current (INa,late) contribute to ventricular arrhythmogenesis under pathological conditions. INa,late was also reported to play a role in chronic atrial fibrillation (AF). The objective of this study was to investigate INa,late in human right atrial cardiomyocytes as a putative drug target for treatment of AF. To activate Na+ channels, cardiomyocytes from transgenic mice which exhibit INa,late (?KPQ), and right atrial cardiomyocytes from patients in sinus rhythm (SR) and AF were voltage clamped at room temperature by 250-ms long test pulses to -30 mV from a holding potential of -80 mV with a 100-ms pre-pulse to -110 mV (protocol I). INa,late at -30 mV was not discernible as deviation from the extrapolated straight line IV-curve between -110 mV and -80 mV in human atrial cells. Therefore, tetrodotoxin (TTX, 10 ?M) was used to define persistent inward current after 250 ms at -30 mV as INa,late. TTX-sensitive current was 0.27±0.06 pA/pF in ventricular cardiomyocytes from ?KPQ mice, and amounted to 0.04±0.01 pA/pF and 0.09±0.02 pA/pF in SR and AF human atrial cardiomyocytes, respectively. With protocol II (holding potential -120 mV, pre-pulse to -80 mV) TTX-sensitive INa,late was always larger than with protocol I. Ranolazine (30 ?M) reduced INa,late by 0.02±0.02 pA/pF in SR and 0.09±0.02 pA/pF in AF cells. At physiological temperature (37°C), however, INa,late became insignificant. Plateau phase and upstroke velocity of action potentials (APs) recorded with sharp microelectrodes in intact human trabeculae were more sensitive to ranolazine in AF than in SR preparations. Sodium channel subunits expression measured with qPCR was high for SCN5A with no difference between SR and AF. Expression of SCN8A and SCN10A was low in general, and lower in AF than in SR. In conclusion, We confirm for the first time a TTX-sensitive current (INa,late) in right atrial cardiomyocytes from SR and AF patients at room temperature, but not at physiological temperature. While our study provides evidence for the presence of INa,late in human atria, the potential of such current as a target for the treatment of AF remains to be demonstrated.

Dataset Information

Calmodulin kinase II regulates atrial myocyte late sodium current, calcium handling, and atrial arrhythmia.

Publications

Calmodulin kinase II regulates atrial myocyte late sodium current, calcium handling, and atrial arrhythmia.

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