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Review
. 2018 Sep 29;19(10):2970.
doi: 10.3390/ijms19102970.

Role of KCa3.1 Channels in Modulating Ca2+ Oscillations during Glioblastoma Cell Migration and Invasion

Luigi Catacuzzeno  1 , Fabio Franciolini  2
Affiliations
Review

Role of KCa3.1 Channels in Modulating Ca2+ Oscillations during Glioblastoma Cell Migration and Invasion

Luigi Catacuzzeno et al. Int J Mol Sci. .

Abstract

Cell migration and invasion in glioblastoma (GBM), the most lethal form of primary brain tumors, are critically dependent on Ca2+ signaling. Increases of [Ca2+]i in GBM cells often result from Ca2+ 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 Ca2+ signaling is further strengthened by the Ca2+ influx from the extracellular space through Ca2+ release-activated Ca2+ (CRAC) currents sustained by Orai/STIM channels, meant to replenish the partially depleted ER. Notably, the elevated cytosolic [Ca2+]i activates the intermediate conductance Ca2+-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 Ca2+ entry through Orai/STIM channels as a result of the increased electromotive (driving) force on Ca2+ influx, ending with the establishment of a recurrent cycle reinforcing the Ca2+ signal. Ca2+ signaling in migrating GBM cells often emerges in the form of intracellular Ca2+ 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 Ca2+ oscillations. In accordance, we recently built a theoretical model of Ca2+ 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 Ca2+ oscillations. Here we review our new theoretical model of Ca2+ oscillations in GBM, upgraded in the light of better knowledge of the KCa3.1 channel kinetics and Ca2+ sensitivity, the dynamics of the Orai/STIM channel modulation, the migration and invasion mechanisms of GBM cells, and their regulation by Ca2+ signals.

Keywords: KCa3.1 channels; calcium oscillations; cell migration; glioblastoma; mathematical model.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Ca2+ oscillations in response to inositol thriphosphate (IP3) increase, with and without Ca2+ influx from extracellular space. (A) Bottom, drawing illustrating the hormone-based production of IP3 that activates the IP3 receptor to release Ca2+ from endoplasmic reticulum (ER). The biphasic effects of cytosolic Ca2+ on IP3 receptor gating (the basic mechanism for Ca2+ oscillations), whereby Ca2+ modulates positively the receptor at low [Ca2+] but negatively at high [Ca2+], is also illustrated. Top, Ca2+ oscillations as produced from the schematics below. Note the decaying trend of Ca2+ spikes due to the absence of Ca2+ influx from extracellular space; (B) Here the drawing has been enriched with a Ca2+ influx apparatus from extracellular space through ER-depletion activated Orai channels on the plasma membrane (bottom), which generates sustained Ca2+ oscillations (top). For clarity, SERCA and PMCA Ca2+ pumps have not been sketched in the drawing, although their activity has always been taken into account. For the same reason, we omitted to draw STIM protein of the ER.
Figure 2
Figure 2
Modulation of Ca2+ oscillations by the KCa3.1 channel. Drawing (C) illustrating the main ion fluxes generating or modulating the Ca2+ oscillations in our model when the KCa3.1 channel is cut off (A) or introduced into the system (B). Please notice the much longer duration (width) and slightly higher amplitude of the Ca2+ oscillations in the presence of KCa3.1 channels.
Figure 3
Figure 3
Ca2+ oscillation development depends on the IP3 concentration and the activity of KCa3.1 channels. (A) Bottom. Bifurcation diagram showing that IP3 concentration determines the establishment of the Ca2+ oscillations. The red dashed line represents the unstable equilibrium [Ca2+]i. The computation was performed with gKCa3.1 = 5 nS. R and S indicate the Hopf bifurcations where Ca2+ oscillations appear and disappear, respectively, upon increasing the IP3 levels. Top. The traces show the temporal changes of the [Ca2+]i for three different concentrations of IP3 (indicated by arrows in the bottom part). (B) Bottom. Plot of the two Hopf bifurcations (R and S) as a function of the IP3 concentration and gKCa3.1. Three different ranges of IP3 concentrations, where the KCa3.1-induced Vm oscillations appear to have different effects in the modulation of Ca2+ oscillations are evidenced (shaded areas; see text). More specifically in the pink region the presence of KCa3.1 channels is necessary for the existence of Ca2+ oscillations, in the light blue region KCa3.1 channels prevents Ca2+ oscillations, and finally in the white region in between KCa3.1 channels modulate the shape and duration of oscillation. Top. Simulated Ca2+ oscillations obtained with two IP3 concentrations (1.5 left and 6.2 μM right, as indicated by the red and blue arrows below) within the regions where removing KCa3.1 channels make Ca2+ oscillations disappear or appear. (Modified from [48].)
Figure 4
Figure 4
Schematic diagram of cell migratory cycle. The classic view of the cell migration process can be split down into four main cyclical steps. The cycle begins with the cell front protrusion, due to the activity of Na+/K+/2Cl− cotransport (yellow) (A) and establishment of adhesion structures (B). The elongated cell then removes/weakens the rear adhesions (C) so that ensuing contraction can pull the rear cell portion forward (D). The concomitant values of [Ca2+]i is indicated by the red portion on the associated Ca2+ oscillation. Vm, ion and water fluxes are also illustrated (see text for details).
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