POSSIBLE WAYS OF REGULATION OF MITOCHONDRIAL KATP CHANNEL

A.V. Agafonov¹, S.M. Grigoriev¹, Yu.Yu. Skarga¹, B.S. Marinov¹, B. Allard² and G.D. Mironova^1 
1Institute of Theoretical and Experimental Biophysics RAS, Pushchino, Russia
²University Claude Bernard, Lyon, France 

Mitochondrial KATP (mitoKATP) channels play an important role in the regulation of mitochondrial functions and are suggested to be involved in cardioprotection.  Study of the regulation of this channel activity is important in order to find means to improve cardiac function in heart disease.  We found that SH-reagents affect mitoKATP channel activity.  When 1-3 mM dithiotreitol (DTT) was added to BLM reconstituted with this channel, the rundown state of the channels were halted.  However, this activation of channels was accompanied by a loss of their selectivity.  The mitoKATP channel is also affected by redox agents, p-diethylaminoethylbenzoate (DEB) and pelargonidine (PD).  DEB increased the probability of channels to be in the opened state.  At micromolar concentrations, DEB reversed the inhibition of channels by ATP and ADP and also prevented their rundown.  In contrast, PD decreased channel activity and diminished the effect of DEB.  The different action of DEB and PD on mitoKATP channel corresponds to their opposite redox properties in reactions with free radicals:  DEB behaves as an electron donor, while PD acts as an electron acceptor.  Another effector of mitoKATP channel activity is pH.  The acidification of medium from pH 7.4 to 5.0 resulted in a significant decrease in integral conductivity of channels.  When pH was turned back to the initial level, the BLM conductivity was restored.  The increase in pH up to 8.5 led to a further increase in conductivity, probably due to the activation of silent channels.  However, when channels were inhibited by ATP, acidification of the medium partially reactivated them.  Earlier it had been found that the function of cytoKATP channels was affected by SH-reagents and depended on pH in a similar manner as found by us in mitoKATP.  Concerning the redox agents, according to our data, the mechanism of the regulation is different.  It was found that the same concentration of DEB didn't reactivate cytoKATP channel in ventricular cardiac myocytes using the patch-clamp technique.

This study was supported by FIRCA PA-9511.

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