title: K(ATP) channel block prevents proteasome inhibitor-induced apoptosis in differentiated PC12 cells.
abstract: Dysfunction of the proteasome system has been suggested to be implicated in neuronal degeneration. Modulation of KATP channels appears to affect the viability of neuronal cells exposed to toxic insults. However, the effect of KATP channel blockers on the neuronal cell death mediated by proteasome inhibition has not been studied. The present study investigated the effect of KATP channel blockers on proteasome inhibitor-induced apoptosis in differentiated PC12 cells and SH-SY5Y cells. 5-Hydroxydecanoate (a selective KATP channel blocker) and glibenclamide (a cell surface and mitochondrial KATP channel inhibitor) reduced the proteasome inhibitor-induced apoptosis. Addition of the KATP channel blockers attenuated the proteasome inhibitor-induced changes in the levels of apoptosis-related proteins, the loss of the mitochondrial transmembrane potential, the increase in the formation of reactive oxygen species and the depletion of glutathione in both cell lines. The results show that KATP channel blockers may attenuate proteasome inhibitor-induced apoptosis in PC12 cells by suppressing activation of the mitochondrial pathway and of the caspase-8- and Bid-dependent pathways. The preventive effect appears to be associated with the inhibition of the formation of reactive oxygen species and the depletion of glutathione. KATP channel blockade appears to prevent proteasome inhibition-induced neuronal cell death.
authors.affiliation: Department of Pharmacology, College of Medicine, and the BK21plus Skin Barrier Network Human Resources Development Team, Chung-Ang University, Seoul 156-756, South Korea.
authors.forename: Yoon Jeong
authors.initials: YJ
authors.lastname: Nam
authors.affiliation: Department of Pharmacology, College of Medicine, and the BK21plus Skin Barrier Network Human Resources Development Team, Chung-Ang University, Seoul 156-756, South Korea.
authors.forename: Da Hee
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, SoonChunHyang University Hospital, Bucheon City, Kyung-Gi-Do 420-767, South Korea.
authors.forename: Min Sung
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, College of Medicine, and the BK21plus Skin Barrier Network Human Resources Development Team, Chung-Ang University, Seoul 156-756, South Korea. Electronic address: leecs@cau.ac.kr.
authors.forename: Chung Soo
authors.initials: CS
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D003652:Decanoic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005978:Glutathione / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology*; D006801:Humans; D006880:Hydroxy Acids / Q000494:pharmacology*; D054086:KATP Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration; D055495:Neurogenesis; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D003652:Decanoic Acids; D006880:Hydroxy Acids; D054086:KATP Channels; D007976:Leupeptins; D026902:Potassium Channel Blockers; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; C052853:5-hydroxydecanoic acid; D046988:Proteasome Endopeptidase Complex; D005978:Glutathione; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D005905:Glyburide
keywords: 2′,7′-Dichlorofluorescin diacetate (Sigma-Aldrich Inc. PubChem CID 77718); 3,3′-Dihexyloxacarbocyanine iodide (Sigma-Aldrich Inc. PubChem CID 103765); 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (Sigma-Aldrich Inc. PubChem CID 64965); 5-Hydroxydecanoate (Sigma-Aldrich Inc. PubChem CID 1825); Apoptosis-related proteins; Glibenclamide (Sigma-Aldrich Inc. PubChem CID 3488); K(ATP) channel blockers; MG115 (EMD-Calbiochem PubChem CID 9868928); MG132 (EMD-Calbiochem PubChem CID 462382); PC12 cells; Proteasome inhibitors; Protection; z-Asp–(OMe)–Gln–Met–Asp(OMe) fluoromethyl ketone (EMD-Calbiochem PubChem CID 644197); z-Ile–Glu–(O-Me)–Thr–Asp(O-Me) fluoromethyl ketone (EMD-Calbiochem PubChem CID 9852164); z-Leu–Glu–(O-Me)–His–Asp(O-Me) fluoromethyl ketone (Sigma-Aldrich Inc. PubChem CID 10032582)