Abstract
Cell migration and invasion in glioblastoma (GBM), the most lethal form of primary brain tumors, are critically dependent on Ca(2+) signaling. Increases of [Ca(2+)](i) in GBM cells often result from Ca(2+) release from the endoplasmic reticulum (ER), promoted by a variety of agents present in the tumor microenvironment and able to activate the phospholipase C/inositol 1,4,5-trisphosphate PLC/IP₃ pathway. The Ca(2+) signaling is further strengthened by the Ca(2+) influx from the extracellular space through Ca(2+) release-activated Ca(2+) (CRAC) currents sustained by Orai/STIM channels, meant to replenish the partially depleted ER. Notably, the elevated cytosolic [Ca(2+)](i) activates the intermediate conductance Ca(2+)-activated K (KCa3.1) channels highly expressed in the plasma membrane of GBM cells, and the resulting K⁺ efflux hyperpolarizes the cell membrane. This translates to an enhancement of Ca(2+) entry through Orai/STIM channels as a result of the increased electromotive (driving) force on Ca(2+) influx, ending with the establishment of a recurrent cycle reinforcing the Ca(2+) signal. Ca(2+) signaling in migrating GBM cells often emerges in the form of intracellular Ca(2+) oscillations, instrumental to promote key processes in the migratory cycle. This has suggested that KCa3.1 channels may promote GBM cell migration by inducing or modulating the shape of Ca(2+) oscillations. In accordance, we recently built a theoretical model of Ca(2+) oscillations incorporating the KCa3.1 channel-dependent dynamics of the membrane potential, and found that the KCa3.1 channel activity could significantly affect the IP₃ driven Ca(2+) oscillations. Here we review our new theoretical model of Ca(2+) oscillations in GBM, upgraded in the light of better knowledge of the KCa3.1 channel kinetics and Ca(2+) sensitivity, the dynamics of the Orai/STIM channel modulation, the migration and invasion mechanisms of GBM cells, and their regulation by Ca(2+) signals.