The mutation L69P in the PAS domain of the hERG potassium channel results in LQTS by trafficking deficiency

Jenewein, Tina; Kanner, Scott A.; Bauer, Daniel; Hertel, Brigitte; Colecraft, Henry M.; Moroni, Anna; Thiel, Gerhard; Kauferstein, Silke

doi:10.1080/19336950.2020.1751522

Cited by 2 publications

(2 citation statements)

References 35 publications

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“…293 cells were collected 48 h after transfection (DNA plasmid only) to examine differences in tail currents of WT, A561V and WT/A561V and the effect of overexpression of ERP57 and CRT on WT/A561V using the patch-clamp technique. A pipette with an end resistance of 2-5 MΩ, when filled with the internal solution, was used to record membrane currents in a whole-cell recording configuration, as described in previous studies ( 21 , 22 ). The electrodes were connected to an Axopatch 700B amplifier (Molecular Devices, LLC), and currents were analog filtered at a frequency of 2 kHz and digitized by an analog-to-digital converter (DigiData1440A; Molecular Devices, LLC).…”

Section: Methodsmentioning

confidence: 99%

Role and mechanism of chaperones calreticulin and ERP57 in restoring trafficking to mutant HERG‑A561V protein

Huang

Zheng

et al. 2021

Int J Mol Med

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Long QT syndrome type 2 is caused by a mutation in the human-ether-a-go-go-related gene (HERG) gene encoding the rapidly activating delayed rectifier K-current. HERG is a key cell membrane glycoprotein; however, whether the maturation process of HERG protein involves key molecules derived from the calnexin (cNX)/calreticulin (cRT) cycle and how these molecules work remains unknown. Using western blotting, the present study screened the key molecules CNX/CRT/endoplasmic reticulum protein 57 (ERP57) involved in this cycle, and it was revealed that the protein expression levels of cNX/cRT/ERP57 in wild-type (WT)/A561V cells were increased compared with those in WT cells (n=3; P<0.05). Additionally, a co-immunoprecipitation experiment was used to reveal that the ability of cNX/ERP57/cRT to interact with HERG was significantly increased in A561V and WT/A561V cells (n=3; P<0.05). A plasmid lacking the bb' domain of ERP57 was constructed and it was demonstrated that the key site of ERP57 binding to CRT and immature HERG protein is the bb' domain. The whole-cell patch-clamp technique detected that the tail current density increased by 46% following overexpression of cRT and by 53% following overexpression of ERP57 in WT/A561V cells. Overexpression of CRT and ERP57 could increased HERG protein levels on the membrane detected by confocal imaging. Furthermore, overexpression of ERP57 and cRT proteins could restore the HERG-A561V mutant protein trafficking process and rescue the dominant-negative suppression of WT. Overall, ERP57/CRT served a crucial role in the HERG-A561V mutant protein trafficking deficiency and degradation process.

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Section: Methodsmentioning

confidence: 99%

Role and mechanism of chaperones calreticulin and ERP57 in restoring trafficking to mutant HERG‑A561V protein

Huang

Zheng

et al. 2021

Int J Mol Med

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“…Mutations in genes encoding ion channels resulting in malfunction of ion channels are among the most common causes. Multiple KCNH 2 mutations can significantly affect the sensitivity of hERG to drug blockade, leading to a prolonged QT interval [ 28 – 30 ]. The risk of QTc prolongation with methadone application is significantly increased in people with CYP2B6 hypometabolism, the first reported genetic factor affecting methadone metabolism and a locus associated with the risk of potentially serious arrhythmias and sudden death [ 31 ].…”

Section: The Risk Factors Of Opioids Mediated Alqtsmentioning

confidence: 99%

Opioids-Induced Long QT Syndrome: A Challenge to Cardiac Health

Hu,

Song,

Huang

et al. 2024

Cardiovasc Toxicol

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The challenge posed by opioid overdose has become a significant concern for health systems due to the complexities associated with drug prohibition, widespread clinical use, and potential abuse. In response, healthcare professionals have primarily concentrated on mitigating the hallucinogenic and respiratory depressant consequences of opioid overdose to minimize associated risks. However, it is crucial to acknowledge that most opioids possess the capacity to prolong the QT interval, particularly in cases of overdose, thereby potentially resulting in severe ventricular arrhythmias and even sudden death if timely intervention is not implemented. Consequently, alongside addressing the typical adverse effects of opioids, it is imperative to consider their cardiotoxicity. To enhance comprehension of the correlation between opioids and arrhythmias, identify potential targets for prompt intervention, and mitigate the hazards associated with clinical utilization, an exploration of the interaction between drugs and ion channels, as well as their underlying mechanisms, becomes indispensable. This review primarily concentrates on elucidating the impact of opioid drugs on diverse ion channels, investigating recent advancements in this domain, and attaining a deeper understanding of the mechanisms underlying the prolongation of the QT interval by opioid drugs, along with potential interventions.

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The mutation L69P in the PAS domain of the hERG potassium channel results in LQTS by trafficking deficiency

Cited by 2 publications

References 35 publications

Role and mechanism of chaperones calreticulin and ERP57 in restoring trafficking to mutant HERG‑A561V protein

Role and mechanism of chaperones calreticulin and ERP57 in restoring trafficking to mutant HERG‑A561V protein

Opioids-Induced Long QT Syndrome: A Challenge to Cardiac Health

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