The cytoprotective action of the potassium channel opener BMS-191095 in C2C12 myoblasts is related to the modulation of calcium homeostasis.
BMS-191095 is an opener of the mitochondrial ATP-regulated potassium channel, which has been shown to provide cytoprotection in models of ischemia-reperfusion induced injury in various tissues. This study aimed at checking the protective action of BMS-191095 under the conditions of oxidative stress or disruption of intracellular calcium homeostasis.


METHODS
The cytoprotective potential of BMS-191095 was tested in C2C12 myoblasts injured by treatment with H(2)O(2) or calcium ionophore A23187. The influence of the opener on intracellular calcium levels, calpain activity and respiration rates were determined.


RESULTS
BMS-191095 protected myoblasts from calcium ionophore A23187-induced injury, but not from H H(2)O(2)-induced injury. A23187-mediated cell damage was also prevented by calpain inhibitor PD 150606. A23187 administration led to a transient increase in cytosolic calcium levels, concomitant activation of calpains and a decrease in state 3 respiration rates, indicating mitochondrial dysfunction. Co-administration of BMS-191095 diminished calpain activation in A23187-treated cells but did not prevent mitochondrial damage. In the presence of BMS-191095, restoration of cytosolic calcium concentrations to basal levels after A23187 treatment was considerably faster which may underly the reduced activation of calpains.


CONCLUSIONS
The BMS-191095-mediated cytoprotection observed in C2C12 myoblasts results probably from modulation of intracellular calcium transients leading to prevention of calpain activation.
Malinska
Dominika
D
Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Warsaw, Poland.
Kulawiak
Bogusz
B
Wrzosek
Antoni
A
Kunz
Wolfram S
WS
Szewczyk
Adam
A
D000179:Acrylates / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D001578:Benzopyrans / Q000494:pharmacology*; D000001:Calcimycin / Q000633:toxicity; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D019610:Cytoprotection / Q000187:drug effects*; D006706:Homeostasis; D006861:Hydrogen Peroxide / Q000633:toxicity; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D032446:Myoblasts / Q000378:metabolism*; D018384:Oxidative Stress; D010101:Oxygen Consumption / Q000187:drug effects; D015221:Potassium Channels / Q000737:chemistry / Q000378:metabolism*
D000179:Acrylates; D000900:Anti-Bacterial Agents; C428117:BMS 191095; D001578:Benzopyrans; D007093:Imidazoles; C100442:PD 150606; D015221:Potassium Channels; D000001:Calcimycin; D006861:Hydrogen Peroxide; D002154:Calpain; D002118:Calcium