Effectors of large-conductance calcium-activated potassium channel modulate glutamate excitotoxicity in organotypic hippocampal slice cultures.
Mitochondria have been suggested as a potential target for cytoprotective strategies. It has been shown that increased K+ uptake mediate by mitochondrial ATP-regulated potassium channels (mitoKATP channel) or large-conductance Ca2+-activated potassium channels (mitoBKCa channel) may provide protection in different models of cell death. Since recent findings demonstrated the presence of BKCa channels in neuronal mitochondria, the goal of the present study was to test the potential neuroprotective effects of BKCa channel modulators. Using organotypic hippocampal slice cultures exposed to glutamate, we demonstrated that preincubation of the slices with the BKCa channel opener NS1619 resulted in decreased neuronal cell death measured as reduced uptake of propidium iodide. This neuroprotective effect was reversed by preincubation with the BKCa channel inhibitors paxilline and Iberiotoxin (IbTx). Moreover, mitochondrial respiration measurements revealed that NS1619 induced an IbTx-sensitive increase in state 2 respiration of isolated brain mitochondria. In addition, electrophysiological patch-clamp studies confirmed the presence of BKCa channels in mitoplasts isolated from embryonic hippocampal cells. Taken together, our results confirm presence of BKCa channel in rat hippocampal neurons mitochondria and suggest putative role for mitoBKCa in neuroprotection.
Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Warsaw, Poland;
Marta
M
Piwońska
Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Warsaw, Poland;
Adam
A
Szewczyk
Project Group Neuropharmacology, Leibniz Institute for Neurobiology, Magdeburg, Germany.
Ullrich H
UH
Schröder
Project Group Neuropharmacology, Leibniz Institute for Neurobiology, Magdeburg, Germany.
Klaus G
KG
Reymann
Department of Biophysics, Warsaw University of Life Sciences - SGGW, Warsaw, Poland; piotr_bednarczyk@sggw.pl.
Iotr
I
Bednarczyk
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D018698:Glutamic Acid / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D015221:Potassium Channels / Q000502:physiology; D017208:Rats, Wistar; D046509:Tissue Culture Techniques
D051036:Large-Conductance Calcium-Activated Potassium Channels; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D018698:Glutamic Acid; D002118:Calcium