Kv1.3 voltage-gated potassium channels link cellular respiration to proliferation through a non-conducting mechanism
Faye Louise Styles, Moza M. Al‐Owais, Jason L. Scragg, Eulashini Chuntharpursat‐Bon, Nishani T. Hettiarachchi, Jonathan D. Lippiat, Aisling Minard, Robin S. Bon, Karen E. Porter, Piruthivi Sukumar, Chris Peers, Lee D. Roberts
Abstract
Cellular energy metabolism is fundamental for all biological functions. Cellular proliferation requires extensive metabolic reprogramming and has a high energy demand. The Kv1.3 voltage-gated potassium channel drives cellular proliferation. Kv1.3 channels localise to mitochondria. Using high-resolution respirometry, we show Kv1.3 channels increase oxidative phosphorylation, independently of redox balance, mitochondrial membrane potential or calcium signalling. Kv1.3-induced respiration increased reactive oxygen species production. Reducing reactive oxygen concentrations inhibited Kv1.3-induced proliferation. Selective Kv1.3 mutation identified that channel-induced respiration required an intact voltage sensor and C-terminal ERK1/2 phosphorylation site, but is channel pore independent. We show Kv1.3 channels regulate respiration through a non-conducting mechanism to generate reactive oxygen species which drive proliferation. This study identifies a Kv1.3-mediated mechanism underlying the metabolic regulation of proliferation, which may provide a therapeutic target for diseases characterised by dysfunctional proliferation and cell growth.