Interaction of ASIC and BK Channels in Human Glioma and its Role in cell Migration and Proliferation

Acid sensing ion channels (ASICs) and large conductance calcium and voltage-activated potassium (BK) channels are expressed through out the nervous system. Studies have showed that ASICs can act as endogenous regulators of BK channels in a pH dependent manner. At physiological pH 7.4 ASIC blocks BK channels, when pH is reduced, ASIC channels are activated and the inhibition of BK is relieved (Petroff et ah, 2008). Our previous studies suggest that pH-dependent relieve of BK inhibition by ASICs increases cell proliferation in glial cells. Extracellular acidosis has been associated with cerebral trauma and brain cancer known as glioma (Andersen et al. 1988 and Wike-Hooley 1984). We hypothesized that the activation of BK channels by a decrease in pH may promote cell migration and invasion in gliomas. Different stages of human glioma cell lines that express both ASIC and BK channels were used. The cells were cultured at physiological pH 7.4 and reduced pH (7.0), in the presence and in the absence of 200 nM of charybdotoxin, a BK channel blocker, and assessed for cell migration and invasion. Our data suggests a complex mechanism for migration and invasion of gliomas. There was evidence supporting the null hypothesis for migration of astrocytoma stage III and IV. Invasion decreased in glioblastoma stage IV with the BK inhibitor. Intratumoral heterogeneity is a hallmark of glioma tumors as evident by our results. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor growth, migration and invasion. This work is supported by the R15 NIH grant to E.P