Mitochondrial K(ATP) channel openers activate the ERK kinase by an oxidant-dependent mechanism

Lobelia Samavati; Martha M Monick; Salih Sanlioglu; Garry R Buettner; Larry W Oberley; Gary W Hunninghake

doi:10.1152/ajpcell.00514.2001

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Mitochondrial K(ATP) channel openers activate the ERK kinase by an oxidant-dependent mechanism

Journal article

Peer reviewed

Mitochondrial K(ATP) channel openers activate the ERK kinase by an oxidant-dependent mechanism

Lobelia Samavati, Martha M Monick, Salih Sanlioglu, Garry R Buettner, Larry W Oberley and Gary W Hunninghake

American Journal of Physiology: Cell Physiology, Vol.283(1), pp.C273-C281

07/2002

DOI: 10.1152/ajpcell.00514.2001

PMID: 12055096

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Abstract

Extracellular signal-regulated kinases (ERKs) are key regulatory proteins that mediate cell survival, proliferation, and differentiation. Reactive oxygen species (ROS) may play a role in activation of the ERK pathway. Because mitochondria are a major source of ROS, we investigated whether mitochondria-derived ROS play a role in ERK activation. Diazoxide, a potent mitochondrial ATP-sensitive K+ (K(ATP)) channel opener, is known to depolarize the mitochondrial membrane potential and cause a reversible oxidation of respiratory chain flavoproteins, thus increasing mitochondrial ROS production. Using THP-1 cells as a model, we postulated that opening mitochondrial K(ATP) channels would increase production of ROS and, thereby, regulate the activity of the ERK kinase. We found that opening mitochondrial K(ATP) channels by diazoxide induced production of ROS as determined by an increased rate of dihydroethidium and dichlorofluorescein fluorescence. This increased production of ROS was associated with increased phosphorylation of ERK kinase in a time-dependent fashion. The MEK inhibitors PD-98059 and U-0126 blocked ERK activation mediated by diazoxide. N-acetylcysteine, but not diphenyleneiodonium, attenuated ERK activation mediated by diazoxide. Adenovirus-mediated overexpression of manganese superoxide dismutase, which is expressed in mitochondria, decreased the rate of dihydroethidium oxidation as well as ERK activation. We conclude that mitochondrial K(ATP) channel openers trigger ERK activation via mitochondria-derived ROS.

Phosphorylation

Cell Line

Gene Transfer Techniques

Pinacidil - pharmacology

Diazoxide - pharmacology

Reactive Oxygen Species - metabolism

Superoxide Dismutase - pharmacology

Humans

Potassium Channels - physiology

Mitochondria - metabolism

Enzyme Activation - drug effects

Potassium Channels - drug effects

Mitogen-Activated Protein Kinases - antagonists & inhibitors

Adenoviridae - genetics

Adenosine Triphosphate - physiology

Genetic Vectors

Enzyme Activation - physiology

Intracellular Membranes - metabolism

Mitogen-Activated Protein Kinases - metabolism

Details

Title: Subtitle: Mitochondrial K(ATP) channel openers activate the ERK kinase by an oxidant-dependent mechanism
Creators: Lobelia Samavati - Department of Medicine, University of Iowa College of Medicine and Veterans Administration Medical Center, Iowa City, Iowa 52242, USA. lobelia-samavati@uiowa.edu
Martha M Monick
Salih Sanlioglu
Garry R Buettner
Larry W Oberley
Gary W Hunninghake
Resource Type: Journal article
Publication Details: American Journal of Physiology: Cell Physiology, Vol.283(1), pp.C273-C281
Publisher: United States
DOI: 10.1152/ajpcell.00514.2001
PMID: 12055096
ISSN: 0363-6143
eISSN: 1522-1563
Language: English
Date published: 07/2002
Academic Unit: Pulmonary, Critical Care, and Occupational Medicine; Radiation Oncology; Internal Medicine
Record Identifier: 9984047890502771

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