© 1999 American Heart Association, Inc.
Original Contribution |
Replacement by Homologous Recombination of the minK Gene With lacZ Reveals Restriction of minK Expression to the Mouse Cardiac Conduction System
From the Departments of Medicine (S.K., T.Y., M.E.A., M.A.M., D.M.R.), Pharmacology (S.K., T.Y., M.E.A., D.M.R.), and Molecular Physiology & Biophysics (K.D.N., M.A.M.), Vanderbilt University School of Medicine, Nashville, Tenn, and Department of Cell Biology and Anatomy (A.W.), Medical University of South Carolina, SC.
Correspondence to Dan M. Roden, MD, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Medical Research Building I, 532C, Nashville, TN 37232-6602. E-mail dan.roden{at}mcmail.vanderbilt.edu
Abstract—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 ß-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. ß-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 ß-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.
Key Words: K+ current • conducting system • development • delayed rectifier
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