title: Proteasomal degradation of Kir6.2 channel protein and its inhibition by a Na+ channel blocker aprindine.
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.
authors.affiliation: Division of Cardiovascular Medicine, The First Department of Internal Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Junichiro
authors.initials: J
authors.lastname: Miake
authors.forename: Tomomi
authors.initials: T
authors.lastname: Notsu
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Sonyama
authors.forename: Norihito
authors.initials: N
authors.lastname: Sasaki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Iitsuka
authors.forename: Masaru
authors.initials: M
authors.lastname: Kato
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Taniguchi
authors.forename: Osamu
authors.initials: O
authors.lastname: Igawa
authors.forename: Akio
authors.initials: A
authors.lastname: Yoshida
authors.forename: Chiaki
authors.initials: C
authors.lastname: Shigemasa
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Hoshikawa
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Kurata
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kuniyasu
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakayama
authors.forename: Nobuo
authors.initials: N
authors.lastname: Inagaki
authors.forename: Eiji
authors.initials: E
authors.lastname: Nanba
authors.forename: Goshi
authors.initials: G
authors.lastname: Shiota
authors.forename: Takayuki
authors.initials: T
authors.lastname: Morisaki
authors.forename: Haruaki
authors.initials: H
authors.lastname: Ninomiya
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hisatome
mesh_terms: 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
chemical_list: D001073:Aprindine; D024661:Potassium Channels, Inwardly Rectifying; D046988:Proteasome Endopeptidase Complex; D026941:Sodium Channel Blockers; D025801:Ubiquitin; D000099161:Kcnj11 Channel