Key result
Voltage-dependent conformational changes of Kv1.3 channels activate cell proliferation and facilitate interaction with the scaffold protein IQGAP3 in HEK and vascular smooth muscle cells.
Why the study?
Although Kv1.3 channels are implicated in cell proliferation, the underlying molecular mechanisms linking Kv1.3 voltage-dependent dynamics to proliferation were poorly identified.
Voltage-dependent conformational changes of Kv1.3 channels are essential for Kv1.3-induced cell proliferation, mediated through interaction with the scaffold protein IQGAP3.
Cautions against clinical translation in vascular disease; extends in vitro mechanistic insights but leaves open in vivo relevance.
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 Ca2+ 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.
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Cidad et al. (2020) studied Cell proliferation. Kv1.3 channel mutations and IQGAP3 manipulation vs. Wild type or control vector was evaluated on Cell proliferation (percentage of cells at S phase quantified using EdU incorporation). Voltage-dependent conformational changes of Kv1.3 channels activate cell proliferation and facilitate interaction with the scaffold protein IQGAP3 in HEK and vascular smooth muscle cells.
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