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, 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.
Tanaka
Hiroaki
H
Division of Cardiovascular Medicine, The First Department of Internal Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan.
Miake
Junichiro
J
Notsu
Tomomi
T
Sonyama
Kazuhiko
K
Sasaki
Norihito
N
Iitsuka
Kazuhiko
K
Kato
Masaru
M
Taniguchi
Shin-ichi
S
Igawa
Osamu
O
Yoshida
Akio
A
Shigemasa
Chiaki
C
Hoshikawa
Yoshiko
Y
Kurata
Yasutaka
Y
Kuniyasu
Akihiko
A
Nakayama
Hitoshi
H
Inagaki
Nobuo
N
Nanba
Eiji
E
Shiota
Goshi
G
Morisaki
Takayuki
T
Ninomiya
Haruaki
H
Kitakaze
Masafumi
M
Hisatome
Ichiro
I
D000818:Animals; D001073:Aprindine / Q000494:pharmacology*; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006868:Hydrolysis; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism; D000099161:Kcnj11 Channel
D001073:Aprindine; D024661:Potassium Channels, Inwardly Rectifying; D046988:Proteasome Endopeptidase Complex; D026941:Sodium Channel Blockers; D025801:Ubiquitin; D000099161:Kcnj11 Channel