PUBLICATION

Conserved Role of the Large Conductance Calcium-Activated Potassium Channel, KCa1.1, in Sinus Node Function and Arrhythmia Risk

Authors
Pineda, S., Nikolova-Krstevski, V., Leimena, C., Atkinson, A.J., Altekoester, A.K., Cox, C.D., Jacoby, A., Huttner, I.G., Ju, Y.K., Soka, M., Ohanian, M., Trivedi, G., Kalvakuri, S., Birker, K., Johnson, R., Molenaar, P., Kuchar, D., Allen, D.G., van Helden, D.F., Harvey, R.P., Hill, A.P., Bodmer, R., Vogler, G., Dobrzynski, H., Ocorr, K., Fatkin, D.
ID
ZDB-PUB-210226-10
Date
2021
Source
Circulation. Genomic and precision medicine   14(2): e003144 (Journal)
Registered Authors
Fatkin, Diane
Keywords
atrium
MeSH Terms
  • Action Potentials/drug effects
  • Animals
  • Atrial Fibrillation/genetics
  • Atrial Fibrillation/pathology*
  • Atrial Function/drug effects
  • Atrial Function/physiology
  • Embryo, Nonmammalian/metabolism
  • Heart Atria/metabolism
  • Heart Atria/pathology
  • Humans
  • Indoles/chemistry
  • Indoles/metabolism
  • Indoles/pharmacology
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/antagonists & inhibitors
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/genetics*
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/metabolism
  • Mice
  • Myocardial Contraction
  • Pedigree
  • Polymorphism, Genetic
  • RNA Interference
  • RNA, Small Interfering/metabolism
  • RNA, Small Interfering/pharmacology
  • Sinoatrial Node/metabolism*
  • Zebrafish
  • Zebrafish Proteins/antagonists & inhibitors
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
33629867 Full text @ Circ Genom Precis Med
Citation
Pineda, S., Nikolova-Krstevski, V., Leimena, C., Atkinson, A.J., Altekoester, A.K., Cox, C.D., Jacoby, A., Huttner, I.G., Ju, Y.K., Soka, M., Ohanian, M., Trivedi, G., Kalvakuri, S., Birker, K., Johnson, R., Molenaar, P., Kuchar, D., Allen, D.G., van Helden, D.F., Harvey, R.P., Hill, A.P., Bodmer, R., Vogler, G., Dobrzynski, H., Ocorr, K., Fatkin, D. (2021) Conserved Role of the Large Conductance Calcium-Activated Potassium Channel, KCa1.1, in Sinus Node Function and Arrhythmia Risk. Circulation. Genomic and precision medicine. 14(2):e003144.
Abstract
Background - KCNMA1 encodes the α-subunit of the large-conductance Ca2+-activated K+ channel, KCa1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of KCa1.1 are limited and KCNMA1 has not been investigated as an AF candidate gene. Methods - The KCNMA1 gene was sequenced in 118 patients with familial AF. The role of KCa1.1 in normal cardiac structure and function was evaluated in humans, mice, zebrafish, and fly. A novel KCNMA1 variant was functionally characterized. Results - A complex KCNMA1 variant was identified in one kindred with AF. To evaluate potential disease mechanisms, we first evaluated the distribution of KCa1.1 in normal hearts using immunostaining and immunogold electron microscopy. KCa1.1 was seen throughout the atria and ventricles in humans and mice, with strong expression in the sinus node. In an ex vivo murine sinoatrial node preparation, addition of the KCa1.1 antagonist, paxilline, blunted the increase in beating rate induced by adrenergic receptor stimulation. Knockdown of the KCa1.1 ortholog, kcnma1b, in zebrafish embryos resulted in sinus bradycardia with dilatation and reduced contraction of the atrium and ventricle. Genetic inactivation of the Drosophila KCa1.1 ortholog, slo, systemically or in adult stages, also slowed the heartbeat and produced fibrillatory cardiac contractions. Electrophysiological characterization of slo-deficient flies revealed bursts of action potentials, reflecting increased events of fibrillatory arrhythmias. Flies with cardiac-specific overexpression of the human KCNMA1 mutant also showed increased heart period and bursts of action potentials, similar to the KCa1.1 loss-of-function models. Conclusions - Our data point to a highly conserved role of KCa1.1 in sinus node function in humans, mice, zebrafish and fly and suggest that KCa1.1 loss of function may predispose to AF.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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