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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)940-946
Number of pages7
JournalCirculation Research
Volume88
Issue number9
StatePublished - May 11 2001

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4-Aminopyridine
Drug Resistance
Homozygote
Muscle Cells
pamidronate
Ambulatory Monitoring
Telemetry
Tetraethylammonium
Gene Targeting
Transgenic Mice
Cardiac Arrhythmias
Proteins
Up-Regulation
RNA
Injections

Keywords

  • Arrhythmias
  • Drug-induced long-QT syndrome
  • Genetically engineered mice
  • Heart
  • Potassium channels

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

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

In: Circulation Research, Vol. 88, No. 9, 11.05.2001, p. 940-946.

Research output: Contribution to journalArticle

London, B, Guo, W, Pan, XH, Lee, JS, Shusterman, V, Rocco, CJ, Logothetis, DA, Nerbonne, JM & Hill, JA 2001, '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, no. 9, pp. 940-946.
London, Barry ; Guo, Weinong ; Pan, Xiang Hua ; Lee, Joon S. ; Shusterman, Vladimir ; Rocco, Christopher J. ; Logothetis, Diomedes A. ; Nerbonne, Jeanne M. ; Hill, Joseph A. / 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. In: Circulation Research. 2001 ; Vol. 88, No. 9. pp. 940-946.
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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.",
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AU - Guo, Weinong

AU - Pan, Xiang Hua

AU - Lee, Joon S.

AU - Shusterman, Vladimir

AU - Rocco, Christopher J.

AU - Logothetis, Diomedes A.

AU - Nerbonne, Jeanne M.

AU - Hill, Joseph A

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N2 - 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.

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KW - Arrhythmias

KW - Drug-induced long-QT syndrome

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