Abstrait

KATP Channels Openers Are Capable of Brain Mitochondrial KATP Channel Opening on Nanomolar Scale Independent of MgATPase Activity

O.V. Akopova

The abundance of mitochondrial ATP-dependent potassium channels (mKATP channels) in neurons implies important physiological role of ATP-sensitive potassium transport in nervous tissues. As it was shown by numerous studies, in CNS mKATP channel was a promising target for the treatment of metabolic stress conditions and neurodegenerative diseases (Busija et al., 2004; Correja et al., 2011). Protection of nervous tissues by mKATP channels openers - diazoxide, pinacidil, nicorandil (KCOs) largely is based on bioenergetic effects of mKATP channels opening, which estimation in brain mitochondria is required for the effective application of KCOs under pathophysiological conditions.

Complex alteration of mitochondrial bioenergetics (ROS production, Ca2+ transport and ATP synthesis) caused by the activation of energy-dissipating potassium cycle and so-called mild uncoupling, in turn is dependent on the sensitivity of mKATP channels to KCOs. Of mKATP channels openers, pinacidil and diazoxide are most widely used ones, but several off-target concentration dependent effects of both drugs were reported, such as inhibition of respiratory complexes I by pinacidil and II by diazoxide, and the inhibition of ATP synthase by diazoxide (Coetzee, 2013). It was remarkable that all reported off-target effects were caused by high micromolar concentrations of KCOs.

From the literature, KATP channels are octameric complexes, which possess four K+ conductant (Kir in sarcolemmal KATP channels) and four receptor subunits (SUR). KATP channels opening by KCOs require the binding of the drugs to the SUR subunit of KATP channels. From the studies on sarcolemmal KATP channels, it is generally known that SUR subunit possesses intrinsic MgATPase activity. So, in numerous studies on isolated mitochondria, it was generally assumed that the presence of Mg²⁺ and ATP was required for mKATP channel opening by KCOs. However, literary data obtained on isolated mitochondria were controversial, and in heart mitochondria the activation of ATP-sensitive K+ transport in the absence of MgATP as well was reported.

Recently (Akopova et al., 2020) we have shown that native liver mKATP channel was activated by diazoxide on sub-micromolar scale in the absence of MgATP, which implies that MgATPase activity was not a prerequisite for mKATP channel activation by diazoxide. So, the aim of this work was to study the effect of diazoxide and pinacidil on mKATP channel activity in isolated brain mitochondria in the absence and the presence of MgATP.