Febrile temperature facilitates hERG/IKr degradation through an altered K+ dependence

Zhao, Yan; Wang, Tingzhong; Guo, Jun; Yang, Tonghua; Li, Wentao; Koichopolos, Jennifer; Lamothe, Shawn M.; Kang, Yudi; Ma, Aiqun; Zhang, Shetuan

doi:10.1016/j.hrthm.2016.06.019

Cited by 17 publications

(20 citation statements)

References 19 publications

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“…Hospitalized COVID-19 patients may suffer from hypoxia, fever, electrolyte abnormalities especially hypokalemia, and viral-or autoimmune-induced myocardial injury (Hu et al, 2020a;Zeng et al, 2020;Clerkin et al, 2020). We have previously demonstrated that hypoxia, fever, hypokalemia, and protease activation can damage or facilitate the damage of hERG function (Lamothe et al, 2017;Lamothe et al, 2016;Guo et al, 2009;Zhao et al, 2016). In fact, while hospitalized COVID-19 patients display respiratory symptoms such as shortness of breath, they also display cardiac arrhythmias (Wang et al, 2020;Du et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

COVID-19 Drugs Chloroquine and Hydroxychloroquine, but Not Azithromycin and Remdesivir, Block hERG Potassium Channels

Szendrey

Guo

et al. 2021

J Pharmacol Exp Ther

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Abbreviations: HEK, human embryonic kidney; hERG, human ether ago go related gene; IC 50 , half maximal inhibitory concentration; I hERG , hERG current; I Kr , rapidly activating delayed rectifier potassium current; I Ks , slowly activating delayed rectifier K + current; LQTS, long QT syndrome; MEM, minimum essential medium; QT c , corrected QT interval; V 1/2 , voltage of half maximal activation. CQ, chloroquine; HCQ, hydroxychloroquine; AZ, azithromycin; RDV, remdesivir.

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Section: Discussionmentioning

confidence: 99%

COVID-19 Drugs Chloroquine and Hydroxychloroquine, but Not Azithromycin and Remdesivir, Block hERG Potassium Channels

Szendrey

Guo

et al. 2021

J Pharmacol Exp Ther

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“…Paired groups of cells were cultured in normoxic or hypoxic conditions for various time periods. After culture, cells were used for electrophysiologic analysis of channel function at room temperature (22 6 1°C) (14,15). The whole-cell patch-clamp method was used to record currents in cell lines, as well as currents and action potentials in neonatal rat ventricular myocytes.…”

Section: Patch-clamp Recordingsmentioning

confidence: 99%

“…The action potentials in neonatal rat ventricular myocytes were recorded in current-clamp mode while various currents were recorded in voltage-clamp mode (14,15). Pipette solution for transient outward potassium current (I to ), inward rectifier potassium current (I K1 ), and action potentials contained (mM) 135 KCl, 10 EGTA, 1 MgCl 2 , 5 MgATP, and 10 HEPES (pH 7.2 with KOH).…”

Section: Patch-clamp Recordingsmentioning

confidence: 99%

“…I Ca-Ba was elicited by depolarizing pulses from the holding potential of 260 mV to voltages between 250 and 30 mV in 10-mV increments. The current upon 0-mV depolarization was used for I Ca-Ba analysis (14,15).…”

Section: Patch-clamp Recordingsmentioning

confidence: 99%

“…6A). I Kr was recorded using I Kr-Cs , with Cs + as a charge carrier to isolate the current from other K + currents (14)(15)(16). Hypoxic culture led to a significant reduction in I Kr-Cs (Fig.…”

Section: Hypoxia Prolongs the Cardiac Action Potential And Selectivelmentioning

confidence: 99%

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Hypoxia reduces mature hERG channels through calpain up‐regulation

Lamothe¹,

Song²,

Guo³

et al. 2017

FASEB j.

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Human -related gene () encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium current () potassium channel, which is important for cardiac repolarization. Impairment of hERG function is the primary cause of acquired long QT syndrome, which predisposes individuals to cardiac arrhythmias and sudden death. Patients with hypoxia due to conditions such as cardiac ischemia or obstructive sleep apnea display increased incidence of cardiac arrhythmias and sudden death. We sought to understand the mechanisms that underlie hypoxia-associated cardiac arrhythmias. Using cell biology and electrophysiologic techniques, we found that hypoxic culture of hERG-expressing human embryonic kidney (HEK) cells and neonatal rat cardiomyocytes reduced hERG current/ and mature ERG channel expression with a concomitant increase in calpain expression. Calpain was actively released into the extracellular milieu and degraded cell-surface hERG. In contrast to hERG, the ether-a-go-go (EAG) channel was not reduced by hypoxic culture. By making chimeric channels between hERG and EAG, we identified that hypoxia-induced calpain degraded hERG by targeting its extracellular S5-pore linker. The scorpion toxin BeKm-1, which is known to selectively bind to the S5-pore linker of hERG, prevented hypoxia-induced hERG reduction. Our data provide novel information about hypoxia-mediated hERG dysfunction and may have biological and clinical implications in hypoxia-associated diseases.-Lamothe, S. M., Song, W., Guo, J., Li, W., Yang, T., Baranchuk, A., Graham, C. H., Zhang, S. Hypoxia reduces mature hERG channels through calpain up-regulation.

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Temperature alters the inotropic, chronotropic and proarrhythmic effects of histamine in atrial muscle preparations from humans and H2-receptor overexpressing mice

Hoffmann

Gergs

Hofmann

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

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We investigated whether hypothermia and hyperthermia can alter the efficacy and potency of histamine at increasing the force of cardiac contractions in mice that overexpress the human H2 receptor only in their cardiac myocytes (labelled H2-TG). Contractile studies were performed in an organ bath on isolated, electrically driven (1 Hz) left atrial preparations and spontaneously beating right atrial preparations from H2-TG mice and wild-type (WT) littermate control mice. The basal beating rate in the right atrial preparations from H2-TG mice was lowered by hypothermia (23 °C) and elevated by hyperthermia (42 °C). Furthermore, the efficacy of histamine (0.01–100 µM) at exerting positive inotropic effects was more severely attenuated in the left and right H2-TG mouse atria under hypothermia and hyperthermia than under normothermia (37 °C). Similarly, the inotropic response to histamine was attenuated under hypothermia and hyperthermia in isolated electrically stimulated (1 Hz) right atrial preparations obtained from humans undergoing cardiac surgery. The phosphorylation state of phospholamban at serine 16 at 23 °C was inferior to that at 37 °C in left atrial preparations from H2-TG mice in the presence of 10 µM histamine. In contrast, in human atrial preparations, the phosphorylation state of phospholamban at serine 16 in the presence of 100 µM histamine was lower at 42 °C than at 37 °C. Finally, under hyperthermia, we recorded more and longer lasting arrhythmias in right atrial preparations from H2-TG mice than in those from WT mice. We conclude that the inotropic effects of histamine in H2-TG mice and in human atrial preparations, as well as the chronotropic effects of histamine in H2-TG mice, are temperature dependent. Furthermore, we observed that, even without stimulation of the H2 receptors by exogenous agonists, temperature elevation can increase arrhythmias in isolated right atrial preparations from H2-TG mice. We propose that H2 receptors play a role in hyperthermia-induced supraventricular arrhythmias in human patients.

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Febrile temperature facilitates hERG/IKr degradation through an altered K+ dependence

Cited by 17 publications

References 19 publications

COVID-19 Drugs Chloroquine and Hydroxychloroquine, but Not Azithromycin and Remdesivir, Block hERG Potassium Channels

COVID-19 Drugs Chloroquine and Hydroxychloroquine, but Not Azithromycin and Remdesivir, Block hERG Potassium Channels

Hypoxia reduces mature hERG channels through calpain up‐regulation

Temperature alters the inotropic, chronotropic and proarrhythmic effects of histamine in atrial muscle preparations from humans and H2-receptor overexpressing mice

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