Regulation of ASIC1 by Ca2+/calmodulin-dependent protein kinase II in human glioblastoma multiforme

Abstract

Abstract. Recent studies have implicated the acid-sensing ion channel 1 (ASIC1), a proton-gated cation channel that belongs to the epithelial sodium channel (ENaC)/Degenerin family, plays an important role in glioma cell migration. Among the ASIC subunits, only ASIC1a has been found be calcium permeable. However, it has not been determined whether Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) regulates ASIC1 in glioblastoma multiforme (GBM). Herein, we report that ASIC1 and CaMKII assemble to form a functional complex at the plasma membrane of GBM cells. We found that migration ability was significantly attenuated in GBM cells that were pre-treated with autocamtide-2-related inhibitory peptide (AIP), a CaMKII-specific inhibitor, or psalmotoxin 1 (PcTX-1), a selective ASIC1 blocker. Furthermore, the inhibitory effect of AIP or PcTX-1 on migration was diminished when ASIC1 was knocked down in GBM cells; when ASIC1 knockdown GBM cells were concurrently treated with these two inhibitors, cell migration was slightly but significantly decreased. Using whole-cell patch-clamp recordings, we detected an amiloride-sensitive current in GBM cells, and this current was significantly inhibited by both PcTX-1 and AIP. Moreover, the magnitude of this current was dramatically decreased when ASIC1 was knocked down in GBM cells. The addition of AIP failed to further decrease the amplitude of this current. Taken together, these data suggest that ASIC1 and CaMKII form a functional complex in GBM cells. Furthermore, it can be concluded that CaMKII regulates the activity of ASIC1, which is associated with the ability of GBM cells to migrate.

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

“…Therefore, inhibition and/or knocking down either CaMK-II or CIC-3 decreased the migration of these cells [242,243]. Similar results, showing that the acid-sensitive non-selective transient ion channel ASIC1a interacts with and is phosphorylated by CaMK-II regulating its activity and controlling glioblastoma cell migration, have been obtained [244]. The combined regulation of CIC-3 and ASIC1a by CaMK-II could be a key feature for net cell volume change during cell migration.…”

Cancer metabolism: New insights into classic characteristics

“…Acid sensing ion channel 1a (ASIC1a) is an H + gated cation channel. Its activation by acidic pH e results in Ca 2+ influx, thereby activating calmodulin-dependent protein kinase II [124] . Ca 2+ influx through ASIC1a also activates PI3K/AKT signaling, which has been associated with resistant to anticancer drugs [125] .…”

Control of cell mechanics by RhoA and calcium fluxes during epithelial scattering

“…74,[77][78][79] CaMKII has been implicated in EMT in development. 80 In xenopus development, CaMKII activation is seen in EMT and migration of fin core cells. 33 Early work in xenopus shows that different types of Wnts act on cell adhesion differently, with Xwnt-5A decreasing cadherin based cell-cell adhesion, and Xwnt-1 increasing cell-cell adhesion.…”