Rab11-dependent Recycling of the Human Ether-a-go-go-related Gene (hERG) Channel

Chen, Jeffery; Guo, Jun; Yang, Tonghua; Li, Wentao; Lamothe, Shawn M.; Kang, Yudi; Szendrey, John A.; Zhang, Shetuan

doi:10.1074/jbc.m115.636324

Cited by 16 publications

(14 citation statements)

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“…To examine the role of Rab11 in the CNO-mediated increase in I hERG , we interfered with Rab11 function by overexpressing a Rab11 DN mutant (Rab11 S25N) in M3Darr-transfected hERG-HEK cells and examined the effect of CNO on I hERG . Overexpression of Rab11 DN reduced I hERG in control cells, indicating that Rab11-contributed hERG homeostasis had been disrupted (Chen et al, 2015). Moreover, overexpression of the Rab11 DN mutant abolished the CNOinduced increase in I hERG (Fig.…”

Section: Resultsmentioning

confidence: 88%

“…**P , 0.01 versus control (Ctrl). b-Arrestin-Mediated hERG Regulation 2013; Chen et al, 2015). It was also reported that stimulation of PIKfyve enhances Rab11-mediated transport of KCNQ1/KCNE1 channels to the membrane (Seebohm et al, 2007).…”

Section: Resultsmentioning

confidence: 99%

“…Channel recycling contributes to the homeostasis of hERG expression level in the plasma membrane (Chen et al, 2015). PIKfyve phosphorylates phosphatidylinositol 3-phosphate to produce phosphatidylinositol 3,5-bisphosphate, a phospholipid implicated in the stability of trafficking vesicles (Berwick et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

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β-Arrestin-Mediated Regulation of the HumanEther-a-go-go-Related Gene Potassium Channel

et al. 2017

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The rapidly activating delayed rectifier K channel (I) is encoded by the human -related gene (), which is important for the repolarization of the cardiac action potential. Mutations in hERG or drugs can impair the function or decrease the expression level of hERG channels, leading to long QT syndrome. Thus, it is important to understand hERG channel trafficking and its regulation. For this purpose, G protein-coupled receptors (GPCRs), which regulate a vast array of cellular processes, represent a useful route. The development of designer GPCRs known as designer receptors exclusively activated by designer drugs (DREADDs) has made it possible to dissect specific GPCR signaling pathways in various cellular systems. In the present study, by expressing an arrestin-biased M3 muscarinic receptor-based DREADD (M3D-arr) in stable hERG-expressing human embryonic kidney (HEK) cells, we demonstrate that -arrestin signaling plays a role in hERG regulation. By exclusively activating M3D-arr using the otherwise inert compound, clozapine-N-oxide, we found that M3D-arr activation increased mature hERG expression and current. Within this paradigm, M3D-arr recruited-arrestin-1 to the plasma membrane, and promoted phosphoinositide 3-kinase-dependent activation of protein kinase B (Akt). The activated Akt acted through phosphatidylinositol 3-phosphate 5-kinase and Rab11 to facilitate hERG recycling to the plasma membrane. Potential -arrestin signaling-mediated increases in hERG and I were also observed in hERG-HEK cells as well as in neonatal rat ventricular myocytes treated with the muscarinic agonist carbachol. These findings provide novel insight into hERG trafficking and regulation.

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Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

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β-Arrestin-Mediated Regulation of the HumanEther-a-go-go-Related Gene Potassium Channel

et al. 2017

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“…In addition to accelerating internalization, ubiquitination of misfolded hERG was found to impair endocytic recycling. It was recently shown that internalized hERG is recycled by a Rab11-dependent mechanism (Lamothe & Zhang, 2013;Chen et al 2015). It is possible that ubiquitination impairs this process, although the involvement of other recycling pathways for internalized hERG channels cannot be ruled out.…”

Section: Peripheral Quality Controlmentioning

confidence: 99%

hERG quality control and the long QT syndrome

Foo

Williamson

Young

et al. 2016

The Journal of Physiology

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Long‐QT syndrome type‐2 (LQT2) is characterized by reduced functional expression of the human ether‐à‐go‐go related (hERG) gene product, resulting in impaired cardiac repolarization and predisposition to fatal arrhythmia. Previous studies have implicated abnormal trafficking of misfolded hERG as the primary mechanism of LQT2, with misfolding being caused by mutations in the hERG gene (inherited) or drug treatment (acquired). More generally, environmental and metabolic stresses present a constant challenge to the folding of proteins, including hERG, and must be countered by robust protein quality control (QC) systems. Disposal of partially unfolded yet functional plasma membrane (PM) proteins by protein QC contributes to the loss‐of‐function phenotype in various conformational diseases including cystic fibrosis (CF) and long‐QT syndrome type‐2 (LQT2). The prevalent view has been that the loss of PM expression of hERG is attributed to biosynthetic block by endoplasmic reticulum (ER) QC pathways. However, there is a growing appreciation for protein QC pathways acting at post‐ER cellular compartments, which may contribute to conformational disease pathogenesis. This article will provide a background on the structure and cellular trafficking of hERG as well as inherited and acquired LQT2. We will review previous work on hERG ER QC and introduce the more novel view that there is a significant peripheral QC at the PM and peripheral cellular compartments. Particular attention is drawn to the unique role of the peripheral QC system in acquired LQT2. Understanding the QC process and players may provide targets for therapeutic intervention in dealing with LQT2.

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“…hERG channels are transcribed in the nucleus; after folding and assembly properly with the assistance of chaperones at the ER (135 kDa), hERG channels enter the Golgi for proper glycosylation (155 kDa) and are finally trafficked to the cell membrane for function [11]. The density of hERG channels on the plasma membrane is controlled by a balance between anterograde trafficking and retrograde degradation [12]. Here, we demonstrate that THIO reduces hERG membrane expression by inhibiting forward trafficking from the ER to the cell surface and subsequently promoting mature channel degradation.…”

Section: Introductionmentioning

confidence: 99%

Thioridazine Induces Cardiotoxicity via Reactive Oxygen Species-Mediated hERG Channel Deficiency and L-Type Calcium Channel Activation

Liu

Zhang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Thioridazine (THIO) is a phenothiazine derivative that is mainly used for the treatment of psychotic disorders. However, cardiac arrhythmias especially QT interval prolongation associated with the application of this compound have received serious attention after its introduction into clinical practice, and the mechanisms underlying the cardiotoxicity induced by THIO have not been well defined. The present study was aimed at exploring the long-term effects of THIO on the hERG and L-type calcium channels, both of which are relevant to the development of QT prolongation. The hERG current (IhERG) and the calcium current (ICa‐L) were measured by patch clamp techniques. Protein levels were analyzed by Western blot, and channel-chaperone interactions were determined by coimmunoprecipitation. Reactive oxygen species (ROS) were determined by flow cytometry and laser scanning confocal microscopy. Our results demonstrated that THIO induced hERG channel deficiency but did not alter channel kinetics. THIO promoted ROS production and stimulated endoplasmic reticulum (ER) stress and the related proteins. The ROS scavenger N-acetyl cysteine (NAC) significantly attenuated hERG reduction induced by THIO and abolished the upregulation of ER stress marker proteins. Meanwhile, THIO increased the degradation of hERG channels via disrupting hERG-Hsp70 interactions. The disordered hERG proteins were degraded in proteasomes after ubiquitin modification. On the other hand, THIO increased ICa‐L density and intracellular Ca2+ ([Ca2+]i) in neonatal rat ventricular cardiomyocytes (NRVMs). The specific CaMKII inhibitor KN-93 attenuated the intracellular Ca2+ overload, indicating that ROS-mediated CaMKII activation promoted calcium channel activation induced by THIO. Optical mapping analysis demonstrated the slowing effects of THIO on cardiac repolarization in mouse hearts. THIO significantly prolonged APD50 and APD90 and increased the incidence of early afterdepolarizations (EADs). In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), THIO also resulted in APD prolongation. In conclusion, dysfunction of hERG channel proteins and activation of L-type calcium channels via ROS production might be the ionic mechanisms for QT prolongation induced by THIO.

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Rab11-dependent Recycling of the Human Ether-a-go-go-related Gene (hERG) Channel

Cited by 16 publications

References 50 publications

β-Arrestin-Mediated Regulation of the HumanEther-a-go-go-Related Gene Potassium Channel

β-Arrestin-Mediated Regulation of the HumanEther-a-go-go-Related Gene Potassium Channel

hERG quality control and the long QT syndrome

Thioridazine Induces Cardiotoxicity via Reactive Oxygen Species-Mediated hERG Channel Deficiency and L-Type Calcium Channel Activation

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