Antidepressant-induced Ubiquitination and Degradation of the Cardiac Potassium Channel hERG

Dennis, Adrienne T.; Nassal, Drew; Deschênes, Isabelle; Thomas, Dierk; Ficker, Eckhard

doi:10.1074/jbc.m111.254367

Cited by 43 publications

(64 citation statements)

References 52 publications

(53 reference statements)

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“…For example, dofetilide and cisapride are proarrhythmic due to their acute blockade of hERG channels [2,3]. Arsenic trioxide, pentamidine and desipramine cause LQTS by altering hERG expression [4,5,6]. Importantly, most of these drugs alter hERG expression by interfering with its trafficking.…”

Section: Introductionmentioning

confidence: 99%

Berberine Induces hERG Channel Deficiency through Trafficking Inhibition

Zhang

Zhi

Huang

et al. 2014

Cell Physiol Biochem

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Aims: The human ether-a-go-go-related gene (hERG) encodes the α subunit of the IKr, which plays an essential role in repolarization of action potentials. hERG channels are targeted by various pro-arrhythmic drugs. Berberine (BBR) was previously found to acutely inhibit hERG currents and prolong action potential duration. The present study aimed to determine long-term effects of BBR on the expression of 135kDa/155kDa hERG and the mechanism. Methods and Results: hERG expression was assessed by western blot. Mature hERG (155 kDa) was reduced, whereas ER-located hERG (135 kDa) was increased by BBR. This indicated that hERG was restricted to the ER and that BBR disrupted channel trafficking. To determine the mechanism of trafficking inhibition, we performed western blot and immunoprecipitation to test folding of hERG by assessing interaction between hERG and Hsp90/Hsp70. Both the expression of Hsp90 and its interaction with hERG were strongly decreased by BBR. These data suggest that BBR reduces channel folding to induce trafficking inhibition. Western blot and confocal imaging were used to further detect whether the unfolded protein response (UPR) was activated. Active ATF6, a marker of the UPR, was activated by BBR. Calnexin and calreticulin, chaperones that are activated by ATF6 to assist channel folding, were also elevated and increasingly colocalized with hERG. These data also demonstrate that the UPR was activated. Immunoprecipitation and western blot assays were performed after BBR treatment to examine ubiquitination and degradation, common endpoints of the UPR. We found that the ER-restricted hERG was ubiquitinized and degraded in the lysosomes and proteasomes. Conclusion: Our study demonstrates that BBR induces hERG channel deficiency by inhibiting channel trafficking after incubation for 24h. Trafficking inhibition activated the UPR, and the ER-restricted hERG was ubiquitinized and degraded in lysosomes and proteasomes.

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Section: Introductionmentioning

confidence: 99%

Berberine Induces hERG Channel Deficiency through Trafficking Inhibition

Zhang

Zhi

Huang

et al. 2014

Cell Physiol Biochem

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“…Amoxapine and desipramine, the tricyclic antidepressants, can cause acquired LQTS through inhibition of I Kr , and they were reported to cause internalization of hERG protein when acutely applied to the HEK cells expressing the hERG channel. Desipramine was also shown to cause poly-ubiquitination of hERG protein, leading to its degradation (26), which is in contrast to the mono-ubiquitination observed when hERG is internalized by low extracellular potassium (see below). In addition, their chronic treatment can disturb forward trafficking of the hERG protein.…”

Section: Hergmentioning

confidence: 55%

“…The mechanism of drug-induced LQTS that can lead to life-threatening arrhythmia is considered to involve (1) blocking of the hERG channel and (2) impairment of forward trafficking of the hERG protein to the cell surface. In addition to these two mechanisms, drug-induced endocytosis of hERG protein was recently reported (26,27). Amoxapine and desipramine, the tricyclic antidepressants, can cause acquired LQTS through inhibition of I Kr , and they were reported to cause internalization of hERG protein when acutely applied to the HEK cells expressing the hERG channel.…”

Section: Hergmentioning

confidence: 99%

Endocytic Regulation of Voltage-Dependent Potassium Channels in the Heart

2012

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Abstract. Understanding the regulation of cardiac ion channels is critical for the prevention of arrhythmia caused by abnormal excitability. Ion channels can be regulated by a change in function (qualitative) and a change in number (quantitative). Functional changes have been extensively investigated for many ion channels including cardiac voltage-dependent potassium channels. By contrast, the regulation of ion channel numbers has not been widely examined, particularly with respect to acute modulation of ion channels. This article briefly summarizes stimulus-induced endocytic regulation of major voltage-dependent potassium channels in the heart. The stimuli known to cause their endocytosis include receptor activation, drugs, and low extracellular [K + ], following which the potassium channels undergo either clathrin-mediated or caveolin-mediated endocytosis. Receptor-mediated endocytic regulation has been demonstrated for Kv1.2, Kv1.5, KCNQ1 (Kv7.1), and Kv4.3, while drug-induced endocytosis has been demonstrated for Kv1.5 and hERG. Low [K + ] o -induced endocytosis might be unique for hERG channels, whose electrophysiological characteristics are known to be under strong influence of [K + ] o . Although the precise mechanisms have not been elucidated, it is obvious that major cardiac voltage-dependent potassium channels are modulated by endocytosis, which leads to changes in cardiac excitability.

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“…Fluoxetine both blocks hERG current and reduces channel trafficking [62] . Even desipramine inhibits the hERG channel by blocking, trafficking inhibition, promoting internalization and accelerating ubiquitinationdegradation [63] . As the majority of the processes involved in biogenesis of the hERG channel are affected by diverse drugs, rescue strategies of hERG dysfunction should be specific to their targets.…”

Section: Alqts Of Herg Channelmentioning

confidence: 99%

Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects

Zhang

Yang

2014

Acta Pharmacol Sin

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The human ether-à-go-go related gene (hERG) potassium channel is an obligatory anti-target for drug development on account of its essential role in cardiac repolarization and its close association with arrhythmia. Diverse drugs have been removed from the market owing to their inhibitory activity on the hERG channel and their contribution to acquired long QT syndrome (LQTS). Moreover, mutations that cause hERG channel dysfunction may induce congenital LQTS. Recently, an increasing number of biochemical and molecular mechanisms underlying hERG-associated LQTS have been reported. In fact, numerous potential biochemical and molecular rescue strategies are hidden within the biogenesis and regulating network. So far, rescue strategies of hERG channel dysfunction and LQTS mainly include activators, blockers, and molecules that interfere with specific links and other mechanisms. The aim of this review is to discuss the rescue strategies based on hERG channel toxicology from the biochemical and molecular perspectives.

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Antidepressant-induced Ubiquitination and Degradation of the Cardiac Potassium Channel hERG

Cited by 43 publications

References 52 publications

Berberine Induces hERG Channel Deficiency through Trafficking Inhibition

Berberine Induces hERG Channel Deficiency through Trafficking Inhibition

Endocytic Regulation of Voltage-Dependent Potassium Channels in the Heart

Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects

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