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Zebrafish cardiac repolarization does not functionally depend on the expression of the hERG1b-like transcript

Resource type
Date created
2023-11-09
Authors/Contributors
Abstract
Zebrafish provide a translational model of human cardiac function. Their similar cardiac electrophysiology enables screening of human cardiac repolarization disorders, drug arrhythmogenicity, and novel antiarrhythmic therapeutics. However, while zebrafish
cardiac repolarization is driven by delayed rectifier potassium channel current (IKr), the relative role of alternate channel transcripts is uncertain. While human ether-a-go-gorelated-gene-1a (hERG1a) is the dominant transcript in humans, expression of the functionally distinct alternate transcript, hERG1b, modifies the electrophysiological and pharmacologic IKr phenotype. Studies of zebrafish IKr are frequently translated without consideration for the presence and impact of hERG1b in humans. Here, we performed phylogenetic analyses of all available KCNH genes from Actinopterygii (ray-finned fishes). Our findings confirmed zebrafish cardiac zkcnh6a as the paralog of human hERG1a (hKCNH2a), but also revealed evidence of a hERG1b (hKCNH2b)-like Nterminally truncated gene, zkcnh6b, in zebrafish. zkcnh6b is a teleost-specific variant that resulted from the 3R genome duplication. qRT-PCR showed dominant expression of zkcnh6a in zebrafish atrial and ventricular tissue, with low levels of zkcnh6b. Functional evauation of zkcnh6b in a heterologous system showed no discernable function under the conditions tested, and no influence on zkcnh6a function during the zebrafish ventricular action potential. Our findings provide the first descriptions of the zkcnh6b gene, and show that, unlike in humans, zebrafish cardiac repolarization does not rely upon coassembly of zERG1a/zERG1b. Given that hERG1b modifies IKr function and drug binding in humans, our findings highlight the need for consideration when translatinghERG variant effects and toxicological screens in zebrafish, which lack a functional
hERG1b-equivalent gene.
Description
This manuscript will be made available in November 2024 due to the embargo period of Springer-Nature Publishing. If you require access to this work prior to November 2024 please email summit@sfu.ca
Embargo period
Accepted date
9 November 2023
Available date
9 November 2024
Identifier
DOI: 10.1007/s00424-023-02875-z d6bdf938-524c-4523-9784-df997d84a83a
Publication details
Publication title
Pflugers Archive - European Journal of Physiology
Document title
Zebrafish cardiac repolarization does not functionally depend on the expression of the hERG1b-like transcript
Date
2023
Copyright statement
Copyright is held by the author(s).
Scholarly level
Peer reviewed?
Yes

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