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Published on: September 30, 2011
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Zebrafish cardiac repolarization does not functionally depend on the expression of the hERG1b-like transcript
Christine E Genge1, Padmapriya Muralidharan1, Jake Kemp1
1Department of Biomedical Physiology and Kinesiology, Simon Fraser University, 8888 University Drive, Burnaby, V5A 1S6, Burnaby, B.C, Canada.
Pflugers Archiv : European Journal of Physiology
|November 7, 2023
Summary
Zebrafish cardiac repolarization research may need reevaluation. Unlike humans, zebrafish lack a functional hERG1b channel, impacting drug screening and translation of cardiac disorder studies.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Genetics
Background:
- Zebrafish are valuable translational models for human cardiac electrophysiology and drug screening.
- Cardiac repolarization in both species is primarily driven by the delayed rectifier potassium channel current (IKr).
- Human cardiac IKr function is modulated by the ether-a-go-go-related-gene-1a (hERG1a) and hERG1b transcripts, influencing drug interactions.
Purpose of the Study:
- To investigate the presence and functional significance of hERG1b-like transcripts in zebrafish.
- To determine if zebrafish cardiac IKr relies on the co-assembly of hERG1a and hERG1b equivalents, similar to humans.
- To assess the implications for translating zebrafish cardiac research to human health.
Main Methods:
- Phylogenetic analysis of KCNH genes in Actinopterygii (ray-finned fishes).
- Identification and characterization of zebrafish KCNH2 paralogs (zkcnh6a and zkcnh6b).
- Quantitative reverse transcription PCR (qRT-PCR) to assess gene expression in zebrafish cardiac tissues.
- Heterologous expression system to functionally evaluate zkcnh6b activity and its impact on zkcnh6a.
Main Results:
- Phylogenetic analysis confirmed zkcnh6a as the zebrafish ortholog of human hERG1a (hKCNH2a).
- A novel, teleost-specific gene, zkcnh6b, was identified as a potential hERG1b (hKCNH2b) paralog in zebrafish.
- zkcnh6b exhibited dominant expression of zkcnh6a in atrial and ventricular tissues, with minimal zkcnh6b expression.
- Functional assays revealed no discernible activity for zkcnh6b alone or in combination with zkcnh6a under tested conditions.
Conclusions:
- Zebrafish possess a hERG1b-like gene (zkcnh6b) but it appears non-functional and does not contribute to cardiac repolarization.
- Unlike humans, zebrafish cardiac repolarization does not depend on the co-assembly of zERG1a and zERG1b.
- These findings necessitate careful consideration when translating zebrafish IKr studies, particularly regarding hERG1b-mediated drug effects and toxicological screens in humans.
