An outwardly rectifying anionic background current in atrial myocytes from the human heart

Li, H.; Zhang, H.; Hancox, Jules C.; Kozlowski, Roland Z.

doi:10.1016/j.bbrc.2007.05.177

Cited by 7 publications

(2 citation statements)

References 24 publications

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“…S16) reported from human atrial cardiomyocytes (54). We added two recently characterized atrial-predominant currents (I K2P (121) and I KCa (122)), updated model formulations of I Kr (123), I Ks (37), I K1 (49, 124), I ClB (125), and I na (49), and included the late Na + current component I NaL (44). Detailed descriptions of updates made to the atrial model of electrophysiology and Ca 2+ is given in SI Appendix, Supplementary Methods .…”

Section: Methodsmentioning

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: Methodsmentioning

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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“…Studies of human cardiac myocytes identified an additional background anion current, termed I ANION , that differed in ionic selectivity from I AB in the guinea pig heart and also was not activated by tefluthrin (Li et al 2007). The molecular basis of this current and its relationship to I AB and other chloride currents in cardiac tissue remains to be clarified.…”

Section: Actions On Chloride Channelsmentioning

confidence: 99%

Molecular mechanisms of pyrethroid insecticide neurotoxicity: recent advances

2011

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Synthetic pyrethroid insecticides were introduced into widespread use for the control of insect pests and disease vectors more than three decades ago. In addition to their value in controlling agricultural pests, pyrethroids are at the forefront of efforts to combat malaria and other mosquito-borne diseases and are also common ingredients of household insecticide and companion animal ectoparasite control products. The abundance and variety of pyrethroid uses contribute to the risk of exposure and adverse effects in the general population. The insecticidal actions of pyrethroids depend on their ability to bind to and disrupt voltage-gated sodium channels of insect nerves. Sodium channels are also important targets for the neurotoxic effects of pyrethroids in mammals but other targets, particularly voltage-gated calcium and chloride channels, have been implicated as alternative or secondary sites of action for a subset of pyrethroids. This review summarizes information published during the past decade on the action of pyrethroids on voltage-gated sodium channels as well as on voltage-gated calcium and chloride channels and provides a critical re-evaluation of the role of these three targets in pyrethroid neurotoxicity based on this information.

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Agonist-like autoantibodies against calcium channel in patients with dilated cardiomyopathy

Xiao

Wang

et al. 2011

Heart Vessels

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The calcium channel may be an important target in the autoimmune pathogenesis of dilated cardiomyopathy (DCM). The presence and function of serum autoantibodies against calcium channels (CC-AAbs) in patients with DCM were studied. Calcium-channel AAbs were detected in 80 patients with DCM and 80 controls by enzyme-linked immunosorbent assay (ELISA). Calcium-channel AAbs were further purified by affinity chromatography for characterization by immunoblotting and immunofluorescence. Voltage-clamp experiments were performed to identify the function of CC-AAbs. The presence of CC-AAbs was shown effectively by ELISA, and CC-AAbs were able specifically to bind to the calcium channel on the myocyte, confirmed by immunoblotting and immunofluorescence. Calcium currents were enhanced by CC-AAbs on Xenopus oocytes expressing human Ca(V)1.2 channels, which suggested CC-AAbs in patients with DCM were agonist-like. Our results suggest there are novel agonist-like CC-AAbs in patients with DCM. Calcium-channel AAbs might play an important role in the pathogenesis of DCM.

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An outwardly rectifying anionic background current in atrial myocytes from the human heart

Cited by 7 publications

References 24 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

Molecular mechanisms of pyrethroid insecticide neurotoxicity: recent advances

Agonist-like autoantibodies against calcium channel in patients with dilated cardiomyopathy

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