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Mechanism of shortened action potential duration in Na+-Ca2+ exchanger knockout mice.
- Source :
-
American journal of physiology. Cell physiology [Am J Physiol Cell Physiol] 2007 Feb; Vol. 292 (2), pp. C968-73. Date of Electronic Publication: 2006 Aug 30. - Publication Year :
- 2007
-
Abstract
- In cardiac-specific Na(+)-Ca(2+) exchanger (NCX) knockout (KO) mice, the ventricular action potential (AP) is shortened. The shortening of the AP, as well as a decrease of the L-type Ca(2+) current (I(Ca)), provides a critical mechanism for the maintenance of Ca(2+) homeostasis and contractility in the absence of NCX (Pott C, Philipson KD, Goldhaber JI. Excitation-contraction coupling in Na(+)-Ca(2+) exchanger knockout mice: reduced transsarcolemmal Ca(2+) flux. Circ Res 97: 1288-1295, 2005). To investigate the mechanism that underlies the accelerated AP repolarization, we recorded the transient outward current (I(to)) in patch-clamped myocytes isolated from wild-type (WT) and NCX KO mice. Peak I(to) was increased by 78% and decay kinetics were slowed in KO vs. WT. Consistent with increased I(to), ECGs from KO mice exhibited shortened QT intervals. Expression of the I(to)-generating K(+) channel subunit Kv4.2 and the K(+) channel interacting protein was increased in KO. We used a computer model of the murine AP (Bondarenko VE, Szigeti GP, Bett GC, Kim SJ, and Rasmusson RL. Computer model of action potential of mouse ventricular myocytes. Am J Physiol Heart Circ Physiol 287: 1378-1403, 2004) to determine the relative contributions of increased I(to), reduced I(Ca), and reduced NCX current (I(NCX)) on the shape and kinetics of the AP. Reduction of I(Ca) and elimination of I(NCX) had relatively small effects on the duration of the AP in the computer model. In contrast, AP repolarization was substantially accelerated when I(to) was increased in the computer model. Thus, the increase in I(to), and not the reduction of I(Ca) or I(NCX), is likely to be the major mechanism of AP shortening in KO myocytes. The upregulation of I(to) may comprise an important regulatory mechanism to limit Ca(2+) influx via a reduction of AP duration, thus preventing Ca(2+) overload in situations of reduced myocyte Ca(2+) extrusion capacity.
- Subjects :
- Animals
Cells, Cultured
Ion Channel Gating
Kv Channel-Interacting Proteins biosynthesis
Mice
Mice, Knockout
Models, Cardiovascular
Patch-Clamp Techniques
Shal Potassium Channels biosynthesis
Sodium-Calcium Exchanger genetics
Ventricular Function
Action Potentials
Calcium physiology
Myocardial Contraction physiology
Myocytes, Cardiac physiology
Shal Potassium Channels physiology
Sodium-Calcium Exchanger physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0363-6143
- Volume :
- 292
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Cell physiology
- Publication Type :
- Academic Journal
- Accession number :
- 16943244
- Full Text :
- https://doi.org/10.1152/ajpcell.00177.2006