Voltage-gated ion channels in cancer cell proliferation

Abstract

Changes of the electrical charges across the surface cell membrane are absolutely necessary to maintain cellular homeostasis in physiological as well as in pathological conditions. The opening of ion channels alter the charge distribution across the surface membrane as they allow the diffusion of ions such as K+, Ca++, Cl.

Keywords: cancer; cell proliferation; membrane potential; voltage gated ion channel.

Figure 1

Schematic representation of possible involvement of different VGIC activity during the cell cycle of cancer cells. According to their expression level, several VGIC have been found playing important roles during the cell cycle. Opening of the voltage-gated Na⁺ and/or Ca⁺⁺ channel move positive charges from the extracellular space to the cytoplasm causing depolarization of the membrane. This event appears to be essential to promote transition from the G0/G1 phase to the S phase of the cell cycle. In contrast, membrane potential during the S phase tends to repolarize due to the opening of K⁺ channels and/or the closing of Ca⁺⁺ and/or Na⁺ channels. Mitosis is associated with more depolarized membrane potential compared to cells in the rest of the S phase. This is possible due to increased cytosolic Na⁺ and/or Ca⁺⁺. Depolarization and augmented Ca⁺⁺ entry will allow stimulation of Ca⁺⁺-activated K⁺ channels and activation of Cl⁻ channels. Both K⁺ and Cl⁻ outward currents are responsible for water leaving the cytoplasm, which leads to a cell shrinkage before cell division. Chronic application of K⁺ channel blockers (e.g., Kv11.1 blocker E4031) or openers (Kv11.1 opener NS1634) leads to changes of the membrane potential in the opposite direction, but both type of drugs cause arrests of the cell cycle in the G0/G1 phase, while blockade of the VGClC arrests the cell cycle in the G2 phase. This suggests that oscillation of the membrane potential is a fundamental event that promotes progression of the cell cycle. ↓ = inward ionic flux; ↑ = outward ionic flux; = no ionic flux.