Rapid component IKr of cardiac delayed rectifier potassium currents in guinea-pig is inhibited by α1-adrenoreceptor activation via protein kinase A and protein kinase C-dependent pathways

Wang, Sen; Xu, Duo; Cai, Jingbo; Ya, Huang; Zou, Jiangang; Cao, Kejiang

doi:10.1016/j.ejphar.2009.02.017

Cited by 25 publications

(31 citation statements)

References 25 publications

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“…The acute effects of PKC activation have been examined in several different experimental systems, using either activators of PKC such as diacylglycerol (DAG)/l-oleoyl-2-acetylsn-glycerol (OAG) and phorbol 12-myristate 13-acetate (PMA) (53, 113,633) or by studying G protein-coupled receptors linked to PKC activation, including TRH receptor (213), angiotensin II receptor AT1 (676), ␣-adrenoceptors (631,671), and muscarinic receptors (113,260,407). Acute activation of PKC typically results in reduced KV11.1 current in oocytes (53, 630, 633) and HEK293 cells (113,513,676), as well as isolated guinea pig ventricular myocytes (671).…”

Section: Pkcmentioning

confidence: 99%

hERG K⁺Channels: Structure, Function, and Clinical Significance

Vandenberg

Perry

Perrin

et al. 2012

Physiological Reviews

591

739

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The human ether-a-go-go related gene (hERG) encodes the pore-forming subunit of the rapid component of the delayed rectifier K(+) channel, Kv11.1, which are expressed in the heart, various brain regions, smooth muscle cells, endocrine cells, and a wide range of tumor cell lines. However, it is the role that Kv11.1 channels play in the heart that has been best characterized, for two main reasons. First, it is the gene product involved in chromosome 7-associated long QT syndrome (LQTS), an inherited disorder associated with a markedly increased risk of ventricular arrhythmias and sudden cardiac death. Second, blockade of Kv11.1, by a wide range of prescription medications, causes drug-induced QT prolongation with an increase in risk of sudden cardiac arrest. In the first part of this review, the properties of Kv11.1 channels, including biogenesis, trafficking, gating, and pharmacology are discussed, while the second part focuses on the pathophysiology of Kv11.1 channels.

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Section: Pkcmentioning

confidence: 99%

hERG K⁺Channels: Structure, Function, and Clinical Significance

Vandenberg

Perry

Perrin

et al. 2012

Physiological Reviews

591

739

View full text Add to dashboard Cite

show abstract

“…Simultaneously, other works proposed that the reduction of the I hERG upon α1-AR stimulation was due to the phosphorylation of the hERG channel by PKA and PKC [16][17][18]. However, when mutation experiments in Xenopus oocytes showed that deletion of most of the consensus phosphorylation sites did not prevent the effect, authors suggested that hERG channels were modulated by PKA and PKC independently of direct phosphorylation [19].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of IhERG/IKr Modulation by α1-Adrenoceptors in HEK293 Cells and Cardiac Myocytes

Urrutia

Alday

Gallego

et al. 2016

Cell Physiol Biochem

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Background: The rapid delayed rectifier K⁺ current (I_Kr), carried by the hERG protein, is one of the main repolarising currents in the human heart and a reduction of this current increases the risk of ventricular fibrillation. α1-adrenoceptors (α1-AR) activation reduces I_Kr but, despite the clear relationship between an increase in the sympathetic tone and arrhythmias, the mechanisms underlying the α1-AR regulation of the hERG channel are controversial. Thus, we aimed to investigate the mechanisms by which α1-AR stimulation regulates I_Kr. Methods: α1-adrenoceptors, hERG channels, auxiliary subunits minK and MIRP1, the non PIP₂-interacting mutant D-hERG (with a deletion of the 883-894 amino acids) in the C-terminal and the non PKC-phosphorylable mutant N-terminal truncated-hERG (NTK-hERG) were transfected in HEK293 cells. Cell membranes were extracted by centrifugation and the different proteins were visualized by Western blot. Potassium currents were recorded by the patch-clamp technique. I_Kr was recorded in isolated feline cardiac myocytes. Results: Activation of the α1-AR reduces the amplitude of I_hERG and I_Kr through a positive shift in the activation half voltage, which reduces the channel availability at physiological membrane potentials. The intracellular pathway connecting the α1-AR to the hERG channel in HEK293 cells includes activation of the Gαq protein, PLC activation and PIP₂ hydrolysis, activation of PKC and direct phosphorylation of the hERG channel N-terminal. The PKC-mediated I_Kr channel phosphorylation and subsequent I_Kr reduction after α1-AR stimulation was corroborated in feline cardiac myocytes. Conclusions: These findings clarify the link between sympathetic nervous system hyperactivity and I_Kr reduction, one of the best characterized causes of torsades de pointes and ventricular fibrillation.

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“…3). PKA-dependent inhibition of transferred TRPC5 channel was reported in HEK cells (Sung et al, 2011), and previous study showed KT5720 inhibits rapid component I(Kr) of cardiac delayed rectifier potassium currents in guinea pigs as well (Wang et al, 2009). However, the effect of PKA inhibition on HCN channel activity remains to be fully explored.…”

Section: Discussionmentioning

confidence: 96%

Novel Role of KT5720 on Regulating Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Activity and Dorsal Root Ganglion Neuron Excitability

Cheng

Zhou²

2013

DNA and Cell Biology

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Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are expressed in dorsal root ganglion (DRG) neurons, which are involved in diverse mechanisms that regulate DRG functions. Protein kinase A (PKA) is an essential kinase that plays a key role in almost all types of cells; it regulates the ion channel activity, the intracellular Ca(2+) concentration, as well as modulates cellular signals transduction. Nevertheless, the effect of PKA inhibition on the HCN channel activity in DRG neuron remains to be elucidated. Here we investigated the impact of PKA inhibition on the HCN channel activity and DRG neurons excitability. Our patch-clamp experiments both under whole-cell and single-channel conditions demonstrated that PKA inhibition with KT5720, a cell membrane permeable PKA-specific inhibitor, significantly attenuated HCN channel currents. Current clamp recording on freshly isolated DRG neurons showed KT5720 reduced overshoot amplitude and enhanced the threshold of the action potential. Moreover, our live-cell Ca(2+) imaging experiments illustrated KT5720 markedly reduced the intracellular Ca(2+) level. Collectively, this is the first report that addresses KT5720 attenuates the HCN channel activity and intracellular Ca(2+), thus reducing DRG neurons excitability. Therefore, our data strongly suggest that PKA is a potential target for curing HCN and DRG neuron relevant diseases.

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Rapid component IKr of cardiac delayed rectifier potassium currents in guinea-pig is inhibited by α1-adrenoreceptor activation via protein kinase A and protein kinase C-dependent pathways

Cited by 25 publications

References 25 publications

hERG K⁺Channels: Structure, Function, and Clinical Significance

hERG K⁺Channels: Structure, Function, and Clinical Significance

Mechanisms of IhERG/IKr Modulation by α1-Adrenoceptors in HEK293 Cells and Cardiac Myocytes

Novel Role of KT5720 on Regulating Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Activity and Dorsal Root Ganglion Neuron Excitability

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Rapid component IKr of cardiac delayed rectifier potassium currents in guinea-pig is inhibited by α1-adrenoreceptor activation via protein kinase A and protein kinase C-dependent pathways

Cited by 25 publications

References 25 publications

hERG K+Channels: Structure, Function, and Clinical Significance

hERG K+Channels: Structure, Function, and Clinical Significance

Mechanisms of IhERG/IKr Modulation by α1-Adrenoceptors in HEK293 Cells and Cardiac Myocytes

Novel Role of KT5720 on Regulating Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Activity and Dorsal Root Ganglion Neuron Excitability

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Product

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hERG K⁺Channels: Structure, Function, and Clinical Significance

hERG K⁺Channels: Structure, Function, and Clinical Significance