Mitochondrial but not plasmalemmal BK channels are hypoxia-sensitive in human glioma.

Tumor cells are resistant to hypoxia but the underlying mechanism(s) of this tolerance remain poorly understood. In healthy brain cells, plasmalemmal Ca2+-activated K+ channels (plasmaBK) function as oxygen sensors and close under hypoxic conditions. Similarly, BK channels in the mitochondrial inner membrane (mitoBK) are also hypoxia sensitive and regulate reactive oxygen species production and also permeability transition pore formation. Both channel populations are therefore well situated to mediate cellular responses to hypoxia. In tumors, BK channel expression increases with malignancy, suggesting these channels contribute to tumor growth; therefore, we hypothesized that the sensitivity of plasmaBK and/or mitoBK to hypoxia differs between glioma and healthy brain cells. To test this, we examined the electrophysiological properties of plasmaBK and mitoBK from a human glioma cell line during normoxia and hypoxia. We observed single channel activities in whole cells and isolated mitoplasts with slope conductance of 199 +/- 8 and 278 +/- 10 pA, respectively. These currents were Ca2+- and voltage-dependent, and were inhibited by the BK channel antagonist charybdotoxin (0.1 mu M). plasmaBK could only be activated at membrane potentials >+40 mV and had a low open probability (NPo) that was unchanged by hypoxia. Conversely, mitoBK were active across a range of membrane potentials (-40 to +40 mV) and their NPo increased during hypoxia. Activating plasmaBK, but not mitoBK induced cell death and this effect was enhanced during hypoxia. We conclude that unlike in healthy brain cells, glioma mitoBK channels, but not plasmaBK channels are oxygen sensitive. GLIA 2014;62:504-513