Journal article
Targeted Replacement of Kv1.5 in the Mouse Leads to Loss of the 4-Aminopyridine-Sensitive Component of IK,slow and Resistance to Drug-Induced QT Prolongation
Circulation research, Vol.88(9), pp.940-946
05/11/2001
DOI: 10.1161/hh0901.090929
PMID: 11349004
Abstract
ABSTRACT—The K channel mKv1.5 is thought to encode a 4-aminopyridine (4-AP)-sensitive component of the current IK,slow in the mouse heart. We used gene targeting to replace mKv1.5 with the 4-AP-insensitive channel rKv1.1 (SWAP mice) and directly test the role of Kv1.5 in the mouse ventricle. Kv1.5 RNA and protein were undetectable, rKv1.1 was expressed, and Kv2.1 protein was upregulated in homozygous SWAP hearts. The density of the K current IK,slow (depolarizations to +40 mV, pA/pF) was similar in left ventricular myocytes isolated from SWAP homozygotes (17±1, n=27) and littermate controls (16±2, n=19). The densities and properties of Ipeak, Ito,f, Ito,s, and Iss were also unchanged. In homozygous SWAP myocytes, the 50-μmol/L 4-AP-sensitive component of IK,slow was absent (n=6), the density of the 20-mmol/L tetraethylammonium-sensitive component of IK,slow was increased (9±1 versus 5±1, P <0.05), and no 100- to 200-nmol/L α-dendrotoxin-sensitive current was found (n=8). APD90 in SWAP myocytes was similar to controls at baseline but did not prolong in response to 30 μmol/L 4-AP. Similarly, QTc (ms) was not prolonged in anesthetized SWAP mice (64±2, homozygotes, n=9; 62±2, controls, n=9), and injection with 4-AP prolonged QTc only in controls (63±1, homozygotes; 72±2, controls;P <0.05). SWAP mice had no increase in arrhythmias during ambulatory telemetry monitoring. Thus, Kv1.5 encodes the 4-AP-sensitive component of IK,slow in the mouse ventricle and confers sensitivity to 4-AP-induced prolongation of APD and QTc. Compensatory upregulation of Kv2.1 may explain the phenotypic differences between SWAP mice and the previously described transgenic mice expressing a truncated dominant-negative Kv1.1 construct.
Details
- Title: Subtitle
- Targeted Replacement of Kv1.5 in the Mouse Leads to Loss of the 4-Aminopyridine-Sensitive Component of IK,slow and Resistance to Drug-Induced QT Prolongation
- Creators
- Barry London - From the Cardiovascular Institute (B.L., X.-h.P., J.S.L., V.S., C.J.R.), University of Pittsburgh, Pittsburgh, Pa; Washington University School of Medicine (W.G., J.M.N.), St. Louis, Mo; Mount Sinai School of Medicine (D.A.L.), New York, NY; and University of Iowa College of Medicine and Department of Veterans Affairs (J.A.H.), Iowa City, IowaWeinong GuoXiang-hua PanJoon LeeVladimir ShustermanChristopher RoccoDiomedes LogothetisJeanne NerbonneJoseph Hill
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.88(9), pp.940-946
- Publisher
- American Heart Association, Inc
- DOI
- 10.1161/hh0901.090929
- PMID
- 11349004
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Language
- English
- Date published
- 05/11/2001
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984025435902771
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