title: Hemin inhibits the large conductance potassium channel in brain mitochondria: a putative novel mechanism of neurodegeneration.
abstract: Intracerebral hemorrhage (ICH) is a pathological condition that accompanies certain neurological diseases like hemorrhagic stroke or brain trauma. Its effects are severely destructive to the brain and can be fatal. There is an entire spectrum of harmful factors which are associated with the pathogenesis of ICH. One of them is a massive release of hemin from the decomposed erythrocytes. It has been previously shown, that hemin can inhibit the large-conductance Ca(2+)-regulated potassium channel in the plasma membrane. However, it remained unclear whether this phenomenon applies also to the mitochondrial large-conductance Ca(2+)-regulated potassium channel. The aim of the present study was to determine the impact of hemin on the activity of the large conductance Ca(2+)-regulated potassium channel in the brain mitochondria (mitoBKCa). In order to do so, we have used a patch-clamp technique and shown that hemin inhibits mitoBKCa in human astrocytoma U-87 MG cell line mitochondria. Since opening of the mitochondrial potassium channels is known to be cytoprotective, we have elucidated whether hemin can attenuate some of the beneficiary effects of potassium channel opening. We have studied the effect of hemin on reactive oxygen species synthesis, and mild mitochondrial uncoupling in isolated rat brain mitochondria. Taken together, our data show that hemin inhibits mitoBKCa and partially abolishes some of the cytoprotective properties of potassium channel opening. Considering the role of the mitoBKCa in cytoprotection, it can be presumed that its inhibition by hemin may be a novel mechanism contributing to the severity of the ICH symptoms. However, the validity of the presented results shall be further verified in an experimental model of ICH.
authors.affiliation: Laboratory of Intracellular Ion Channels, Department of Biochemistry, Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland; Department of Epileptology, University of Bonn, 25 Sigmund-Freud Street, D-53105 Bonn, Germany.
authors.forename: Bartłomiej
authors.initials: B
authors.lastname: Augustynek
authors.affiliation: Department of Epileptology, University of Bonn, 25 Sigmund-Freud Street, D-53105 Bonn, Germany.
authors.forename: Alexei P
authors.initials: AP
authors.lastname: Kudin
authors.affiliation: Laboratory of Intracellular Ion Channels, Department of Biochemistry, Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland; Department of Biophysics, Warsaw University of Life Sciences, 159 Nowoursynowska Street, 02-776 Warsaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Bednarczyk
authors.affiliation: Laboratory of Intracellular Ion Channels, Department of Biochemistry, Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland. Electronic address: a.szewczyk@nencki.gov.pl.
authors.forename: Adam
authors.initials: A
authors.lastname: Szewczyk
authors.affiliation: Department of Epileptology, University of Bonn, 25 Sigmund-Freud Street, D-53105 Bonn, Germany.
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
mesh_terms: D000818:Animals; D001254:Astrocytoma / Q000473:pathology; D001562:Benzimidazoles / Q000494:pharmacology; D001921:Brain / Q000648:ultrastructure*; D002118:Calcium / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006427:Hemin / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D026902:Potassium Channel Blockers; D017382:Reactive Oxygen Species; C086491:NS 1619; D006427:Hemin; C064719:iberiotoxin; D006861:Hydrogen Peroxide; D002118:Calcium
keywords: Hemin; Intracerebral hemorrhage; Mitochondria; Mitochondrial BK(Ca) channel; Neurodegeneration; ROS synthesis