Proteasomal degradation of Kir6.2 channel protein and its inhibition by a Na+ channel blocker aprindine |
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Authors: | Tanaka Hiroaki Miake Junichiro Notsu Tomomi Sonyama Kazuhiko Sasaki Norihito Iitsuka Kazuhiko Kato Masaru Taniguchi Shin-ichi Igawa Osamu Yoshida Akio Shigemasa Chiaki Hoshikawa Yoshiko Kurata Yasutaka Kuniyasu Akihiko Nakayama Hitoshi Inagaki Nobuo Nanba Eiji Shiota Goshi Morisaki Takayuki Ninomiya Haruaki Kitakaze Masafumi Hisatome Ichiro |
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Institution: | Division of Cardiovascular Medicine, The First Department of Internal Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan. |
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Abstract: | ATP-sensitive K+ channels (K(ATP):SUR2A+Kir6.2) play a pivotal role in cardiac protection against ischemia and reperfusion injury. When expressed in COS cells, Kir6.2 was short-lived with a half-life time of 1.9 h. The half-life time of Kir6.2 was prolonged by proteasome inhibitors MG132, ALLN, proteasome inhibitor 1, and lactacystine, but not at all by a lysosomal inhibitor chloroquine. MG132 also increased the level of ubiquitinated Kir6.2 without affecting its localization in the endoplasmic reticulum and Golgi apparatus. In electrophysiological recordings, MG132 augmented nicorandil-activated K(ATP) currents in COS cells expressing SUR2A and Kir6.2 as well as the same currents in neonatal rat cardiomyocytes. Like MG132, a Na+ channel blocker aprindine prolonged the half-life time of Kir6.2 and augmented K(ATP). Finally, both aprindine and MG132 inhibited the 20S proteasome activity in vitro. These results suggest a novel activity of aprindine to enhance K(ATP) currents by inhibiting proteasomal degradation of Kir 6.2 channels, which may be beneficial in the setting of cardiac ischemia. |
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Keywords: | Kir6 2 Proteasome Aprindine |
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