Replacement by Homologous Recombination of the minK Gene With lacZ Reveals Restriction of minK Expression to the Mouse Cardiac Conduction System

• Published in: Circulation research 1999-02, Vol.84 (2), p.146-152
• Main Authors: Kupershmidt, Sabina, Yang, Tao, Anderson, Mark E, Wessels, Andy, Niswender, Kevin D, Magnuson, Mark A, Roden, Dan M
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; beta-Galactosidase - analysis; Biological and medical sciences; Cardiac dysrhythmias; Cardiology. Vascular system; Cardiotonic Agents - pharmacology; Electrocardiography - drug effects; Gene Expression Regulation, Developmental - drug effects; Gene Targeting; Heart; Heart Conduction System - metabolism; Isoproterenol - pharmacology; Lac Operon; Long QT Syndrome - genetics; Medical sciences; Mice; Mice, Knockout; Potassium Channels - genetics; Potassium Channels, Voltage-Gated; Recombination, Genetic; Staining and Labeling
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.84.2.146

The minK gene encodes a 129-amino acid peptide the expression of which modulates function of cardiac delayed rectifier currents (IKr and IKs), and mutations in minK are now recognized as one cause of the congenital long-QT syndrome. We have generated minK-deficient mice in which the bacterial lacZ gene has been substituted for the minK coding region such that beta-galactosidase expression is controlled by endogenous minK regulatory elements. In cardiac myocytes isolated from wild-type neonatal mice, IKs is rarely recorded, while IKr is common. In minK (-/-) myocytes, IKs is absent and IKr is significantly reduced and its deactivation slowed; these results further support a role for minK in modulating both IKs and IKr. Despite these changes, ECGs in (+/+) and (-/-) animals are no different at adult and at neonatal stages. ECG responses to isoproterenol are also similar in the 2 groups. beta-Galactosidase staining in postnatal minK (-/-) hearts is highly restricted, to the sinus-node region, caudal atrial septum, and proximal conducting system. Moreover, as early as embryonal day 11, segmentally restricted beta-galactosidase expression is observed in the portions of the sinoatrial and atrioventricular junctions that are thought to give rise to the conducting system, thereby implicating minK expression as an early event in conduction system development. More generally, the restricted nature of minK expression in the mouse heart suggests species-specific roles of this gene product in mediating the electrophysiological properties of the heart. (Circ Res. 1999;84:146-152.)