<i>β</i>-Arrestin-Mediated Regulation of the Human<i>Ether-a-go-go</i>-Related Gene Potassium Channel

Sangoi, Matthew G; Lamothe, Shawn M.; Guo, Jun; Yang, Tonghua; Li, Wentao; Avery, Ellen G.; Fisher, John T.; Zhang, Shetuan

doi:10.1124/mol.116.108035

Cited by 7 publications

(5 citation statements)

References 65 publications

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“…hERG1 translocation is controlled by the trimeric G protein Gαi3, through the PI3K/Akt pathway. The implication of Akt is consistent with previous reports ( Zhang et al, 2003 ; Sangoi et al, 2017 ; Wang et al, 2019 ), whereas the possible involvement of the chaperon SigmaR ( Crottès, et al, 2011 ) in our model remains to be determined. Gαi3 activation is driven by the non-receptor GEF girdin ( Garcia-Marcos et al, 2015 ).…”

Section: Discussionsupporting

confidence: 93%

Integrins regulate hERG1 dynamics by girdin-dependent Gαi3: signaling and modeling in cancer cells

Duranti,

Iorio,

Bagni

et al. 2023

Life Sci. Alliance

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The hERG1 potassium channel is aberrantly over expressed in tumors and regulates the cancer cell response to integrin-dependent adhesion. We unravel a novel signaling pathway by which integrin engagement by the ECM protein fibronectin promotes hERG1 translocation to the plasma membrane and its association with β1 integrins, by activating girdin-dependent Gαi3 proteins and protein kinase B (Akt). By sequestering hERG1, β1 integrins make it avoid Rab5-mediated endocytosis, where unbound channels are degraded. The cycle of hERG1 expression determines the resting potential (Vrest) oscillations and drives the cortical f-actin dynamics and thus cell motility. To interpret the slow biphasic kinetics of hERG1/β1 integrin interplay, we developed a mathematical model based on a generic balanced inactivation–like module. Integrin-mediated cell adhesion triggers two contrary responses: a rapid stimulation of hERG1/β1 complex formation, followed by a slow inhibition which restores the initial condition. The protracted hERG1/β1 integrin cycle determines the slow time course and cyclic behavior of cell migration in cancer cells.

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Section: Discussionsupporting

confidence: 93%

Integrins regulate hERG1 dynamics by girdin-dependent Gαi3: signaling and modeling in cancer cells

Duranti,

Iorio,

Bagni

et al. 2023

Life Sci. Alliance

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“…The results of this study suggest that enhanced β-arrestin2 expression may produce dramatic changes in IKr characteristics. These results are in agreement with those of previous studies (12). It is likely that enhanced β-arrestin2 expression will mitigate AP prolongation during α1-adrenoceptor stimulation.…”

Section: Discussionsupporting

confidence: 93%

“…It was only recently that UNC9994 (a β-arrestin2 selective agonist) was reported to modulate G protein-coupled inward rectifier potassium channel in Xenopus oocytes (26). A β-arrestin-mediated increase in hERG/IKr has been reported in human embryonic kidney cells (12). It is important to note that, while heterologous expression systems are powerful due to their adaptability to molecular manipulation, they may not exactly generalize the actual signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

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Î²-Arrestin2 regulates the rapid component of delayed rectifier K+ currents and cardiac action potential of guinea pig cardiomyocytes after adrenergic stimulation

Shi

Zhou

et al. 2019

Cell Mol Biol (Noisy-le-grand)

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A decrease in the rapid component of delayed rectifier potassium current (IKr) during chronic heart failure (CHF) prolongs action potential (AP), and plays a key role in the pathogenesis of ventricular arrhythmias. β-Arrestin2 has been shown to restore the inotropic reserve of β-adrenergic regulation, but little or nothing is known about its effect on intrinsic channel. This study investigated the role of β-arrestin2 in the regulation of cardiac hERG/IKr potassium channel and AP during chronic adrenergic stimulation. Single left ventricular myocytes were isolated from guinea pig heart, and were transfected with adenovirus encoding β-arrestin2, or β-arrestin2 siRNA or an empty adenovirus. Cell cultures containing 10 nM isoproterenol, 1 nM phenylephrine or vehicle alone (control medium) were electro-physiologically examined after 48 h of incubation. Action potential duration at 50 and 90 % of repolarization (APD 50 and APD 90 ) were measured using whole-cell patch-clamp recording. Sustained adrenergic stimulation significantly reduced the density of the IKr current (p < 0.001). β-Arrestin2 expression in cell cultures treated with isoproterenol or phenylephrine was significantly downregulated after adrenergic stimulation (p < 0.001). Overexpression of β-arrestin2 significantly attenuated isoproterenol or phenylephrine-induced reduction in IKr current. It also prevented the phenylephrine-induced prolongation of AP (p < 0.05 for APD 50 and p < 0.001 for APD 90 ), but did not significantly affect AP profile after exposure of the cardiomyocytes to isoproterenol (p > 0.05). Therefore, Increased levels of β-Arrestin2 weaken dysregulation of IKr current and prevent excessive AP prolongation, making it an effective anti-arrhythmic strategy.

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“…The synthesis process of HERG channels is slow, and hERG recycling back to the membrane is essential to maintain its stable surface expression and ensure fast recovery of the repolarization duration 33 . Trafficking toward the membrane is notably mediated by the GTPase RAB11 [33][34][35][36] . Our protein fractioning data showed higher recruitment of RAB11 to the membrane in HS iPS-CMs than in LS iPS-CMs after treatment with sotalol.…”

Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 99%

CAVIN1-Mediated Endocytosis: A Novel Mechanism Underlying The Interindividual Variability In Drug-Induced Long QT

Sayed

Pereira

Pénard

et al. 2023

Preprint

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Background: Drug-induced QT prolongation (diLQT) is a feared side-effect as exposing susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily attributed to unintended drug interactions with cardiac ion channels, notably the hERG channels that generate the repolarizing current (IKr) and thereby regulate the late repolarization phase. There is an important inter-individual susceptibility to develop diLQT which is of unknown origin but can be reproduced in patient-specific iPSC-derived cardiomyocytes (iPS-CMs). Objective: We aimed to investigate the dynamics of hERG channels in response to sotalol and to identify regulators of the susceptibility to developing diLQT. Methods: We measured electrophysiological activity and cellular distribution of hERG channels after hERG blocker treatment in iPS-CMs derived from patients with highest or lowest sensitivity (HS or LS) to sotalol administration in vivo (i.e., based on the measure of the maximal change in QT interval 3 hours after administration). Specific small-interfering RNAs (siRNA) and CAVIN1-T2A-GFP adenovirus were used to manipulate CAVIN1 expression. Results: While HS and LS iPS-CMs showed similar electrophysiological characteristics at the baseline, the late repolarization phase was prolonged, and IKr significantly decreased after exposure of HS iPS-CMs to low sotalol concentrations. IKr reduction was caused by a rapid translocation of hERG channel from the plasma membrane to the cytoskeleton upon sotalol application. This phenomenon was suppressed by blocking active endocytosis using dynasore. CAVIN1, essential for caveolae biogenesis, was two-times more expressed in HS iPS-CMs and its knockdown using siRNA decreased their sensitivity to sotalol. CAVIN1 overexpression in LS iPS-CMs using adenovirus showed reciprocal effects. Mechanistically, we found that treatment with sotalol promoted trafficking of the hERG channel from the plasma membrane to the cytoskeleton through caveolae and in a manner dependent on CAVIN1 expression. CAVIN1 silencing reduced the number of caveolae at the membrane and abrogated the internalization of hERG channel in sotalol-treated HS iPS-CMs. CAVIN1 also controlled cardiomyocyte responses to other hERG blockers such as E4031, vandetanib, and clarithromycin. Conclusions: Our study identifies unbridled turnover of the potassium channel hERG as a mechanism supporting the inter-individual susceptibility underlying diLQT development and demonstrates how this phenomenon is finely tuned by CAVIN1.

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

Cited by 7 publications

References 65 publications

Integrins regulate hERG1 dynamics by girdin-dependent Gαi3: signaling and modeling in cancer cells

Integrins regulate hERG1 dynamics by girdin-dependent Gαi3: signaling and modeling in cancer cells

Î²-Arrestin2 regulates the rapid component of delayed rectifier K+ currents and cardiac action potential of guinea pig cardiomyocytes after adrenergic stimulation

CAVIN1-Mediated Endocytosis: A Novel Mechanism Underlying The Interindividual Variability In Drug-Induced Long QT

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