PUBLICATION

POPDC1 Variants Cause Atrioventricular Node Dysfunction and Arrhythmogenic Changes in Cardiac Electrophysiology and Intracellular Calcium Handling in Zebrafish

Authors
Stoyek, M.R., Doane, S.E., Dallaire, S.E., Long, Z.D., Ramia, J.M., Cassidy-Nolan, D.L., Poon, K.L., Brand, T., Quinn, T.A.
ID
ZDB-PUB-240328-18
Date
2024
Source
Genes   15(3): (Journal)
Registered Authors
Brand, Thomas, Quinn, Alex, Stoyek, Matthew
Keywords
Popeye domain-containing (Popdc) genes, action potential, arrhythmias, autonomic nervous system, calcium transient, cyclic adenosine monophosphate (cAMP), heart rate, optogenetics
MeSH Terms
  • Adult
  • Animals
  • Arrhythmias, Cardiac/genetics
  • Atrioventricular Block*/complications
  • Atrioventricular Node/metabolism
  • Calcium*/metabolism
  • Cardiac Conduction System Disease
  • Electrophysiologic Techniques, Cardiac/adverse effects
  • Humans
  • Zebrafish/genetics
  • Zebrafish/metabolism
PubMed
38540339 Full text @ Genes (Basel)
Citation
Stoyek, M.R., Doane, S.E., Dallaire, S.E., Long, Z.D., Ramia, J.M., Cassidy-Nolan, D.L., Poon, K.L., Brand, T., Quinn, T.A. (2024) POPDC1 Variants Cause Atrioventricular Node Dysfunction and Arrhythmogenic Changes in Cardiac Electrophysiology and Intracellular Calcium Handling in Zebrafish. Genes. 15(3):.
Abstract
Popeye domain-containing (POPDC) proteins selectively bind cAMP and mediate cellular responses to sympathetic nervous system (SNS) stimulation. The first discovered human genetic variant (POPDC1S201F) is associated with atrioventricular (AV) block, which is exacerbated by increased SNS activity. Zebrafish carrying the homologous mutation (popdc1S191F) display a similar phenotype to humans. To investigate the impact of POPDC1 dysfunction on cardiac electrophysiology and intracellular calcium handling, homozygous popdc1S191F and popdc1 knock-out (popdc1KO) zebrafish larvae and adult isolated popdc1S191F hearts were studied by functional fluorescent analysis. It was found that in popdc1S191F and popdc1KO larvae, heart rate (HR), AV delay, action potential (AP) and calcium transient (CaT) upstroke speed, and AP duration were less than in wild-type larvae, whereas CaT duration was greater. SNS stress by β-adrenergic receptor stimulation with isoproterenol increased HR, lengthened AV delay, slowed AP and CaT upstroke speed, and shortened AP and CaT duration, yet did not result in arrhythmias. In adult popdc1S191F zebrafish hearts, there was a higher incidence of AV block, slower AP upstroke speed, and longer AP duration compared to wild-type hearts, with no differences in CaT. SNS stress increased AV delay and led to further AV block in popdc1S191F hearts while decreasing AP and CaT duration. Overall, we have revealed that arrhythmogenic effects of POPDC1 dysfunction on cardiac electrophysiology and intracellular calcium handling in zebrafish are varied, but already present in early development, and that AV node dysfunction may underlie SNS-induced arrhythmogenesis associated with popdc1 mutation in adults.
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