Proteasomal degradation of Kir6.2 channel protein and its inhibition by a Na + channel blocker aprindine

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, prot...

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Published in:	Biochemical and biophysical research communications Vol. 331; no. 4; pp. 1001 - 1006
Main 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
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 17-06-2005
Subjects:	Animals Aprindine Aprindine - pharmacology Cells, Cultured Endoplasmic Reticulum - metabolism Golgi Apparatus - metabolism Hydrolysis Kir6.2 Potassium Channels, Inwardly Rectifying - antagonists & inhibitors Potassium Channels, Inwardly Rectifying - metabolism Proteasome Proteasome Endopeptidase Complex - metabolism Rats Sodium Channel Blockers - pharmacology Ubiquitin - metabolism Aprindine Kir6.2 Proteasome
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0006-291X 1090-2104
DOI:	10.1016/j.bbrc.2005.04.011