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(Circulation Research. 2001;88:940.)
© 2001 American Heart Association, Inc.

Integrative Physiology

Targeted Replacement of Kv1.5 in the Mouse Leads to Loss of the 4-Aminopyridine–Sensitive Component of I_K,slow and Resistance to Drug-Induced QT Prolongation

Barry London, Weinong Guo, Xiang-hua Pan, Joon S. Lee, Vladimir Shusterman, Christopher J. Rocco, Diomedes A. Logothetis, Jeanne M. Nerbonne, Joseph A. Hill

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, Iowa.

Correspondence to Barry London, MD, PhD, Cardiovascular Institute, University of Pittsburgh, BST 1744, 200 Lothrop St, Pittsburgh, PA 15213. E-mail londonb{at}msx.upmc.edu

Abstract—The K⁺ channel mKv1.5 is thought to encode a 4-aminopyridine (4-AP)–sensitive component of the current I^K,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 I_K,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 I_peak, I_to,f, I_to,s, and I_ss were also unchanged. In homozygous SWAP myocytes, the 50-µmol/L 4-AP–sensitive component of IK,slowwas absent (n=6), the density of the 20-mmol/L tetraethylammonium-sensitive component of I_K,slow was increased (9±1 versus 5±1, P<0.05), and no 100- to 200-nmol/L -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 I_K,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.

Key Words: potassium channels • heart • genetically engineered mice • drug-induced long-QT syndrome • arrhythmias

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