Oxidation of multiple methionine residues impairs rapid sodium channel inactivation

被引:66
作者
Kassmann, Mario [1 ]
Hansel, Alfred [1 ]
Leipold, Enrico [1 ]
Birkenbeil, Jan [1 ]
Lu, Song-Qing [1 ]
Hoshi, Toshinori [2 ]
Heinemann, Stefan H. [1 ]
机构
[1] Univ Jena, Ctr Mol Biomed, Dept Biophys, D-07745 Jena, Germany
[2] Univ Penn, Dept Physiol, Philadelphia, PA 19104 USA
来源
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY | 2008年 / 456卷 / 06期
基金
美国国家卫生研究院;
关键词
sodium channel; Na+ channel; inactivation; methionine oxidation; chloramine-T; lucifer yellow; patch clamp;
D O I
10.1007/s00424-008-0477-6
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Reactive oxygen species (ROS) readily oxidize the sulfur-containing amino acids cysteine and methionine (Met). The impact of Met oxidation on the fast inactivation of the skeletal muscle sodium channel Na(V)1.4 expressed in mammalian cells was studied by applying the Met-preferring oxidant chloramine-T or by irradiating the ROS-producing dye Lucifer Yellow in the patch pipettes. Both interventions dramatically slowed down inactivation of the sodium channels. Replacement of Met in the Ile-Phe-Met inactivation motif with Leu (M1305L) strongly attenuated the oxidizing effect on inactivation but did not eliminate it completely. Mutagenesis of Met1470 in the putative receptor of the inactivation lid also markedly diminished the oxidation sensitivity of the channel, while that of other conserved Met residues in intracellular linkers connecting the membrane-spanning segments (442, 1139, 1154, 1316, 1469) were of minor importance. The results of mutagenesis, assays of other Na-V channel isoforms (Na(V)1.2, Na(V)1.5, Na(V)1.7), and the kinetics of the oxidation-induced removal of inactivation collectively indicate that multiple Met residues need to be oxidized to completely impair inactivation. This arrangement using multiple Met residues confers a finely graded oxidative modulation of Na-V channels and allows organisms to adapt to a variety of oxidative stress conditions, such as ischemic reperfusion.
引用
收藏
页码:1085 / 1095
页数:11
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