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The transient outward current in mice lacking the potassium channel gene Kv1.4
Author(s) -
London Barry,
Wang Dao W.,
Hill Joseph A.,
Bennett Paul B.
Publication year - 1998
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1111/j.1469-7793.1998.171bo.x
Subject(s) - cardiac transient outward potassium current , potassium channel , repolarization , patch clamp , knockout mouse , chemistry , membrane potential , myocyte , biophysics , microbiology and biotechnology , medicine , endocrinology , gene , electrophysiology , biology , biochemistry
1 The transient outward current ( I to ) plays a prominent role in the repolarization phase of the cardiac action potential. Several K + channel genes, including Kv1.4 , are expressed in the heart, produce rapidly inactivating currents when heterologously expressed, and may be the molecular basis of I to . 2 We engineered mice homozygous for a targeted disruption of the K + channel gene Kv1.4 and compared I to in wild‐type (Kv1.4 +/+ ), heterozygous (Kv1.4 +/‐ ) and homozygous ‘knockout’ (Kv1.4 −/− ) mice. Kv1.4 RNA was truncated in Kv1.4 −/− mice and protein expression was absent. 3 Adult myocytes isolated from Kv1.4 +/+ , Kv1.4 +/− and Kv1.4 −/− mice had large rapidly inactivating outward currents. The peak current densities at 60 mV (normalized by cellular capacitance, in pA pF −1 ; means ± s.e.m.) were 53.8 ± 5.3, 45.3 ± 2.2 and 44.4 ± 2.8 in cells from Kv1.4 +/+ , Kv1.4 +/− and Kv1.4 −/− mice, respectively ( P < 0.02 for Kv1.4 +/+ vs. Kv1.4 −/− ). The steady‐state values (800 ms after the voltage clamp step) were 30.9 ± 2.9, 26.9 ± 3.8 and 23.5 ± 2.2, respectively ( P < 0.02 for Kv1.4 +/+ vs. Kv1.4 −/− ). The inactivating portion of the current was unchanged in the targeted mice. 4 The voltage dependence and time course of inactivation were not changed by targeted disruption of Kv1.4 . The mean best‐fitting V ½ (membrane potential at 50 % inactivation) values for myocytes from Kv1.4 +/+ , Kv1.4 +/− and Kv1.4 −/− mice were ‐53.5 ± 3.7, ‐51.1 ± 2.6 and ‐54.2 ± 2.4 mV, respectively. The slope factors ( k ) were ‐10.1 ± 1.4, ‐8.8 ± 1.4 and ‐9.5 ± 1.2 mV, respectively. The fast time constants for development of inactivation at ‐30 mV were 27.8 ± 2.2, 26.2 ± 5.1 and 19.6 ± 2.1 ms in Kv1.4 +/+ , Kv1.4 +/− and Kv1.4 −/− myocytes, respectively. At +30 mV, they were 35.5 ± 2.6, 30.0 ± 2.1 and 28.7 ± 1.6 ms, respectively. The time constants for the rapid phase of recovery from inactivation at ‐80 mV were 32.5 ± 8.2, 23.3 ± 1.8 and 39.0 ± 3.7 ms, respectively. 5 Nearly the entire inactivating component as well as more than 60 % of the steady‐state outward current was eliminated by 1 m m 4‐aminopyridine in Kv1.4 +/+ , Kv1.4 +/− and Kv1.4 −/− myocytes. 6 Western blot analysis of heart membrane extracts showed no significant upregulation of the Kv4 subfamily of channels in the targeted mice. 7 Thus, Kv1.4 is not the molecular basis of I to in adult murine ventricular myocytes.