Electrophysiological Characterization of an Alternatively Processed ERG K
            <sup>+</sup>
            Channel in Mouse and Human Hearts

Lees‐Miller, James P.; Kondo, Colleen; Wang, Li; Duff, Henry J.

doi:10.1161/01.res.81.5.719

Cited by 192 publications

(223 citation statements)

References 15 publications

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“…Western blot analysis indicates that both forms are expressed in human ventricle, and co-immunoprecipitation indicates that canine erg1a and erg1b subunits associate together in the T-tubules of cardiomyocytes (11). Erg1a homotetramers, with a fully intact N-terminal "eag" domain deactivate very slowly, whereas erg1b homotetramers deactivate ϳ10ϫ faster (12)(13)(14). It has been estimated that hERG1b represents about ϳ10 -25% of the total hERG1 mRNA in the human heart (14).…”

mentioning

confidence: 99%

Concerted All-or-none Subunit Interactions Mediate Slow Deactivation of Human ether-à-go-go-related Gene K+ Channels

Thomson

Hansen

Sanguinetti

2014

Journal of Biological Chemistry

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Background:The N terminus of hERG1 subunits modulates the rate of channel deactivation. Results: A single mutant subunit in a concatenated hERG1 tetramer accelerates channel deactivation. Conclusion: All four subunits cooperate fully to slow the rate of hERG1 channel deactivation. Significance: A single subunit harboring a mutation in the PAS domain or S6 segment can alter the gating properties of a tetrameric hERG1 channel.

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confidence: 99%

Concerted All-or-none Subunit Interactions Mediate Slow Deactivation of Human ether-à-go-go-related Gene K+ Channels

Thomson

Hansen

Sanguinetti

2014

Journal of Biological Chemistry

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“…Cardiac I Kr , a repolarizing current in the heart (4), is produced by heteromeric assemblies of human ether-à-go-go-related gene (hERG) 1a and 1b subunits (5)(6)(7)(8)(9)(10). Perturbations of I Kr by congenital mutations in the KCNH2/hERG1 gene or by drug block can prolong the ventricular action potential and associated QT interval to cause long QT syndrome and sudden cardiac death (11)(12)(13).…”

mentioning

confidence: 99%

“…Perturbations of I Kr by congenital mutations in the KCNH2/hERG1 gene or by drug block can prolong the ventricular action potential and associated QT interval to cause long QT syndrome and sudden cardiac death (11)(12)(13). hERG 1a and 1b subunits are encoded by alternate transcripts that arise from distinct promoters within the hERG1 locus (7,8). The subunits are identical except for their N termini, which differ in length and primary sequence.…”

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confidence: 99%

Cotranslational association of mRNA encoding subunits of heteromeric ion channels

Liu

Jones

Lange

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Oligomers of homomeric voltage-gated potassium channels associate early in biogenesis as the nascent proteins emerge from the polysome. Less is known about how proteins emerging from different polysomes associate to form hetero-oligomeric channels. Here, we report that alternate mRNA transcripts encoding human ether-à-go-go-related gene (hERG) 1a and 1b subunits, which assemble to produce ion channels mediating cardiac repolarization, are physically associated during translation. We show that shRNA specifically targeting either hERG 1a or 1b transcripts reduced levels of both transcripts, but only when they were coexpressed heterologously. Both transcripts could be copurified with an Ab against the nascent hERG 1a N terminus. This interaction occurred even when translation of 1b was prevented, indicating the transcripts associate independent of their encoded proteins. The association was also demonstrated in cardiomyocytes, where levels of both hERG transcripts were reduced by either 1a or 1b shRNA, but native KCNE1 and ryanodine receptor 2 (RYR2) transcripts were unaffected. Changes in protein levels and membrane currents mirrored changes in transcript levels, indicating the targeted transcripts were undergoing translation. The physical association of transcripts encoding different subunits provides the spatial proximity required for nascent proteins to interact during biogenesis, and may represent a general mechanism facilitating assembly of heteromeric protein complexes involved in a range of biological processes.KCNH2 | hERG | cotranslational assembly | microtranslatome | hERG 1a/1b

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“…Subsequently, alternate transcripts of KCNH2 in mouse and human heart were shown to encode two subunits: 1a (the original isolate) and 1b (6,7). In the hERG 1b transcript, an alternate 5′ exon replaces 1a exons 1-5, resulting in a shorter, unique N terminus that lacks a Per-Arnt-Sim (PAS) domain (also known as the ether-à-go-go domain) (8,9).…”

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confidence: 99%

hERG 1b is critical for human cardiac repolarization

Jones¹,

Liu²,

Vaidyanathan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

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The human ether-à-go-go-related gene (hERG; or KCNH2) encodes the voltage-gated potassium channel underlying I Kr , a repolarizing current in the heart. Mutations in KCNH2 or pharmacological agents that reduce I Kr slow action potential (AP) repolarization and can trigger cardiac arrhythmias associated with long QT syndrome. Two channel-forming subunits encoded by KCNH2 (hERG 1a and 1b) are expressed in cardiac tissue. In heterologous expression systems, these subunits avidly coassemble and exhibit biophysical and pharmacological properties distinct from those of homomeric hERG 1a channels. Despite these findings, adoption of hERG 1a/1b heteromeric channels as a model for cardiac I Kr has been hampered by the lack of evidence for a direct functional role for the 1b subunit in native tissue. In this study, we measured I Kr and APs at physiological temperature in cardiomyocytes derived from human induced pluripotent stem cells (iPSC-CMs). We found that specific knockdown of the 1b subunit using shRNA caused reductions in 1b mRNA, 1b protein levels, and I Kr magnitude by roughly one-half. AP duration was increased and AP variability was enhanced relative to controls. Early afterdepolarizations, considered cellular substrates for arrhythmia, were also observed in cells with reduced 1b expression. Similar behavior was elicited when channels were effectively converted from heteromers to 1a homomers by expressing a fragment corresponding to the 1a-specific N-terminal Per-Arnt-Sim domain, which is omitted from hERG 1b by alternate transcription. These findings establish that hERG 1b is critical for normal repolarization and that loss of 1b is proarrhythmic in human cardiac cells.T he human ether-à-go-go-related gene (hERG; or KCNH2) encodes the voltage-gated potassium channel underlying a native cardiac current known as I Kr (1, 2). Mutations in the gene or drugs that block the channel can diminish I Kr and slow ventricular repolarization, thus prolonging the QT interval on the surface electrocardiogram and causing long QT syndrome (LQTS) (1-3). Individuals with LQTS have an increased risk for torsades de pointes arrhythmia, syncope, and sudden cardiac death. Since 2005, a cell-based assay expressing the hERG 1a isoform as a proxy for I Kr has been the cornerstone of drug safety screening for new drug development (4). Thus, whether current drug safety assays accurately represent the native channel is of paramount importance.The first studies of heterologously expressed hERG channels described biophysical (1, 2) and pharmacological (2, 5) properties uniquely characteristic of cardiac I Kr . Subsequently, alternate transcripts of KCNH2 in mouse and human heart were shown to encode two subunits: 1a (the original isolate) and 1b (6, 7). In the hERG 1b transcript, an alternate 5′ exon replaces 1a exons 1-5, resulting in a shorter, unique N terminus that lacks a Per-Arnt-Sim (PAS) domain (also known as the ether-à-go-go domain) (8, 9). In heterologous systems, hERG 1b subunits avidly associate with hERG 1a but fail as homomer...

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Electrophysiological Characterization of an Alternatively Processed ERG K ⁺ Channel in Mouse and Human Hearts

Cited by 192 publications

References 15 publications

Concerted All-or-none Subunit Interactions Mediate Slow Deactivation of Human ether-à-go-go-related Gene K+ Channels

Concerted All-or-none Subunit Interactions Mediate Slow Deactivation of Human ether-à-go-go-related Gene K+ Channels

Cotranslational association of mRNA encoding subunits of heteromeric ion channels

hERG 1b is critical for human cardiac repolarization

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Electrophysiological Characterization of an Alternatively Processed ERG K + Channel in Mouse and Human Hearts

Cited by 192 publications

References 15 publications

Concerted All-or-none Subunit Interactions Mediate Slow Deactivation of Human ether-à-go-go-related Gene K+ Channels

Concerted All-or-none Subunit Interactions Mediate Slow Deactivation of Human ether-à-go-go-related Gene K+ Channels

Cotranslational association of mRNA encoding subunits of heteromeric ion channels

hERG 1b is critical for human cardiac repolarization

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Electrophysiological Characterization of an Alternatively Processed ERG K ⁺ Channel in Mouse and Human Hearts