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Transgenic mice overexpressing human KvLQT1 dominant-negative isoform. Part I: Phenotypic characterisation
S Demolombe1, G Lande, F Charpentier
1INSERM U533, Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Moléculaires G & R Laennec, Faculté de Médecine, 1 rue Gaston Veil, 44035 Nantes cedex 01, France.
Cardiovascular Research
|May 4, 2001
Summary
Engineered a KCNQ1 dominant-negative mouse model to study cardiac potassium channels. This model revealed KvLQT1 channels are crucial for heart rhythm regulation, impacting repolarization, sinus node function, and AV node conduction.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Genetics
Background:
- The KCNQ1 gene encodes the KvLQT1 potassium channel, essential for the cardiac delayed rectifier current I(Ks).
- KCNQ1 mutations are a leading cause of congenital long QT syndrome.
- A dominant-negative KCNQ1 isoform was previously identified.
Purpose of the Study:
- To develop an in vivo model of KvLQT1 channel disruption.
- To investigate the role of KvLQT1 channels in cardiac electrophysiology.
Main Methods:
- Overexpression of a dominant-negative KCNQ1 subunit in transgenic mice using the alpha-myosin heavy chain promoter.
- Phenotypic analysis, ECG, His recordings, patch-clamp electrophysiology, and RNase protection assays.
Main Results:
- Transgenic mice exhibited prolonged QT intervals and sinus node dysfunction.
- Atrio-ventricular block, including Wenckebach phenomenon, was observed.
- Prolonged QT correlated with action potential duration and reduced K+ current density, with altered K+ channel expression.
Conclusions:
- The KvLQT1 channel plays a significant role in cardiac repolarization in mice.
- KvLQT1 channels are vital for sinus node automaticity.
- KvLQT1 channels influence impulse propagation through the atrio-ventricular node.