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Titolo:
Targeted replacement of Kv1.5 in the mouse leads to loss of the 4-aminopyridine-sensitive component of I-K,I-slow and resistance to drug-induced QT prolongation
Autore:
London, B; Guo, WN; Pan, XH; Lee, JS; Shusterman, V; Rocco, CJ; Logothetis, DA; Nerbonne, JM; Kill, JA;
Indirizzi:
Univ Pittsburgh, Cardiovasc Inst, Pittsburgh, PA 15213 USA Univ Pittsburgh Pittsburgh PA USA 15213 sc Inst, Pittsburgh, PA 15213 USA Washington Univ, Sch Med, St Louis, MO USA Washington Univ St Louis MO USA shington Univ, Sch Med, St Louis, MO USA Mt Sinai Sch Med, New York, NY USA Mt Sinai Sch Med New York NY USAMt Sinai Sch Med, New York, NY USA Univ Iowa, Coll Med, Iowa City, IA USA Univ Iowa Iowa City IA USAUniv Iowa, Coll Med, Iowa City, IA USA Dept Vet Affairs, Iowa City, IA USA Dept Vet Affairs Iowa City IA USADept Vet Affairs, Iowa City, IA USA
Titolo Testata:
CIRCULATION RESEARCH
fascicolo: 9, volume: 88, anno: 2001,
pagine: 940 - 946
SICI:
0009-7330(20010511)88:9<940:TROKIT>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
RECTIFIER K+ CURRENT; TRANSIENT OUTWARD CURRENT; HUMAN ATRIAL MYOCYTES; KV4 ALPHA-SUBUNIT; POTASSIUM CHANNEL; LONG-QT; VENTRICULAR ARRHYTHMIAS; TRANSGENIC MICE; HUMAN HEART; EXPRESSION;
Keywords:
potassium channels; heart; genetically engineered mice; drug-induced long-QTF syndrome; arrhythmias;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
32
Recensione:
Indirizzi per estratti:
Indirizzo: London, B Univ Pittsburgh, Cardiovasc Inst, BST 1744,200 Lothrop St, Pittsburgh, PA 15213 USA Univ Pittsburgh BST 1744,200 Lothrop St Pittsburgh PA USA 15213
Citazione:
B. London et al., "Targeted replacement of Kv1.5 in the mouse leads to loss of the 4-aminopyridine-sensitive component of I-K,I-slow and resistance to drug-induced QT prolongation", CIRCUL RES, 88(9), 2001, pp. 940-946

Abstract

The K+ channel mKv1.5 is thought to encode a 4-aminopyridine (4-AP)-sensitive component of the current I-K,I-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 wore undetectable, rKv1.1 was expressed, and Kv2.1 protein was upregulated in homozygous SWAP hearts, The density of the K+ current I-K,I-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,I-f, I-to,I-s, and I-ss were also unchanged. In homozygous SWAP myocytes, the 50-mu mol/L 4-AP-sensitive component of I-K,I-slow was absent (n=6), the density of The 20-mmol/L tetraethylammonium-sensitive component of I-K,I-slow was increased (9 +/-1 versus, 5 +/-1, P <0.05), and no 100- to 200-nmol/L alpha -dendrotoxin-sensitive current was found (n=8). APD(90) in SWAP myocytes was similar to controls at baseline but did not prolong in response to 30 mu mol/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,I-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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Documento generato il 12/07/20 alle ore 08:38:54