Voltage‐dependent conformational changes of Kv1.3 channels activate cell proliferation

Abstract

The voltage-dependent potassium channel Kv1.3 has been implicated in proliferation in many cell types, based on the observation that Kv1.3 blockers inhibited proliferation. By modulating membrane potential, cell volume, and/or Ca 2+ influx, K + channels can influence cell cycle progression. Also, noncanonical channel functions could contribute to modulate cell proliferation independent of K + efflux. The specificity of the requirement of Kv1.3 channels for proliferation suggests the involvement of molecule-specific interactions, but the underlying mechanisms are poorly identified. Heterologous expression of Kv1.3 channels in HEK cells has been shown to increase proliferation independently of K + fluxes. Likewise, some of the molecular determinants of Kv1.3-induced proliferation have been located in the C-terminus region, where individual point mutations of putative phosphorylation sites (Y447A and S459A) abolished Kv1.3-induced proliferation. Here, we investigated the mechanisms linking Kv1.3 channels to proliferation exploring the correlation between Kv1.3 voltage-dependent molecular dynamics and cell cycle progression. Using transfected HEK cells, we analyzed both the effect of changes in resting membrane potential on Kv1.3-induced proliferation and the effect of mutated Kv1.3 channels with altered voltage dependence of gating. We conclude that voltage-dependent transitions of Kv1.3 channels enable the activation of proliferative pathways. We also found that Kv1.3 associated with IQGAP3, a scaffold protein involved in proliferation, and that membrane depolarization facilitates their interaction. The functional contribution of Kv1.3-IQGAP3 interplay to cell proliferation was demonstrated both in HEK cells and in vascular smooth muscle cells. Our data indicate that voltage-dependent conformational changes of Kv1.3 are an essential element in Kv1.3-induced proliferation.

Kv1.3 Channel Inhibition Limits Uremia-Induced Calcification in Mouse and Human Vascular Smooth Muscle

“…Alteration of Kv1.3 expression during transition from contractile to proliferating phenotype has been previously described. 21 , 27 , 32 Kv1.3 can modulate cell proliferation by several alternative mechanisms, including (1) controlling membrane potential and thus the driving force for Ca 2+ entry; (2) acting as a voltage sensor that transduces membrane potential into biochemical signals 36 ; (3) altering the channelosome balance relatively to Kv1.5 expression. 32 The last two mechanisms have been linked to increased VSMC proliferation after injury.…”

Diversification of Potassium Currents in Excitable Cells via Kvβ Proteins

“…While the precise mechanisms underlying this role of Kv1.3 in proliferation are still unclear, there is a clear role for voltage-dependent changes in the channel conformation that activate pro-proliferative pathways independent of the transmembrane ion flux [ 116 ]. This may involve depolarization-induced interactions with proliferation regulatory protein IQGAP3 and downstream Ras-dependent ERK activation [ 117 ]. Parallel to changes in ion channel expression, robust metabolic changes also occur during phenotypic modulation of vascular smooth muscle; transformation from contractile to synthetic smooth muscle is associated with enhanced glycolysis, LDH activity, and glutamine utilization that facilitate proliferation and migration [ 118 , 119 ].…”

Beta-Titanium Alloy Covered by Ferroelectric Coating–Physicochemical Properties and Human Osteoblast-Like Cell Response

“…The release of Ba from BaTiO3 coating was also confirmed in the present study, and its negative effect on the cell proliferation cannot be excluded. Barium is known as a classic permeant blocker of potassium channels [54], which are implicated in proliferation of many cell types including osteoblasts [55,56]. In a study by Ciofani et al (2010), the number of H9C2 rat cardiomyocytes in cultures exposed to BaTiO3-containing polylysine nanoparticles decreased with increasing number of these nanoparticles [57].…”