Modulation of the calcium-activated BK-channel of the inner mitochondrial membrane by hypoxia

It is known from stroke that hypoxia has dramatic effects on neuronal energy metabolism and on cell survival. It was unknown, however, whether the mitochondrial ion channels are susceptible to hypoxia though they are involved in ischemic preconditioning and in the intrinsic cascade of apoptotic cell death. Therefore, we studied the effect of hypoxia on several parameters of the current through the Ca2+ -activated potassium channel (BK) from inner mitochondrial membrane of human glioblastom cells (LN229) and of embryonic rat astrocytes. We prepared vesicles of inner mitochondrial membrane (mitoplasts) by hypotonic treatment of the mitochondria and measured single-channel currents by means of patch-clamp techniques. Hypoxia was induced either by bubbling the solutions for up to 2h by nitrogen or by applying different concentrations of dithionite or cyanide. While the single-channel conductance in astrocytes was unchanged by hypoxia (after nitrogen-bubbling), we found a considerably increased open probability (Po) of the channel at low Ca2+ -concentrations (1µM). At higher concentrations (200µM) this effect of hypoxia was absent. As the BK has a modulating function on the permeability transition pore which is involved in the intrinsic pathway of apoptosis, activity of the BK may be an important response to hypoxia.

Supported by the State of Sachsen-Anhalt and the BMFT.