Expression and Role of the Intermediate-Conductance Calcium-Activated Potassium Channel KCa3.1 in Glioblastoma

Figure 1

Schematic drawing illustrating the main properties and roles of the KCa3.1 channel expressed in glioblastoma cells. KCa3.1 channels can be activated by elevations of the [Ca²⁺]_i originating either from the PLC- and IP₃-dependent Ca²⁺ release from intracellular stores triggered by G-protein-coupled receptors or from Ca²⁺ influx through TRPC channels. The KCa3.1 channel activity can also be regulated by several kinases, such as PI3K, PKC, and PKA. The expression of the channel is under the control of the RTK/ERK/MAPK-dependent AP-1 and REST transcription factors acting on the Kcnn4 gene and further depends on the balance between endo- and exocytosis of KCa3.1 channel-containing vesicles. The drawing further highlights the two basic mechanisms sustained by the KCa3.1 channels: (i) inserted in the Ca²⁺ regulation module, in synergy with Ca²⁺ permeable channels (a TRPC in the scheme), the KCa3.1 channel amplifies the Ca²⁺ signals by hyperpolarizing the membrane, thus increasing the driving force for Ca²⁺ influx; (ii) in the cell volume regulation module, in synergy with Cl and aquaporin channels, the KCa3.1 channel controls the cell volume by contributing to changes in the intracellular osmolarity and water content. Inset: Top: KCa3.1 subunit topology showing the six transmembrane domain signature. The calmodulin-binding domain and the histidine phosphorilation site at the C-terminus have been indicated. Bottom: Schematic drawing showing the homotetrameric nature of functional KCa3.1 channels.