The electric fence to cell‐cycle progression: Do local changes in membrane potential facilitate disassembly of the primary cilium?

Abstract

Kv10.1 is a voltage-gated potassium channel relevant for tumor biology, but the underlying mechanism is still unclear. We propose that Kv10.1 plays a role coordinating primary cilium disassembly with cell cycle progression through localized changes of membrane potential at the ciliary base. Most non-dividing cells display a primary cilium, an antenna-like structure important for cell physiology. The cilium is disassembled when the cell divides, which requires an increase of Ca concentration and a redistribution of phospholipids in its basal region, both of which would be facilitated by local hyperpolarization. Cells lacking Kv10.1 show impaired ciliary disassembly and delayed entrance into mitosis. Kv10.1 is predominantly expressed during G2/M, a critical period for ciliary resorption, and localizes to the ciliary base and vesicles associated with the centrosome. This could explain the influence of Kv10.1 in cell proliferation, as well as phenotypic features of patients carrying gain of function mutations in the gene.

Inhibition of Kv10.1 Channels Sensitizes Mitochondria of Cancer Cells to Antimetabolic Agents

“…At this point, we cannot rule out that ion flow through Kv10.1 is only a part of the signaling mechanism. Active Kv10.1 channels participate in primary cilium disassembly [16,43], a process that is also impaired by mitochondrial stress [44]. Both ciliary homeostasis [45] and mitochondrial dynamics [46] require calcium signaling, and active potassium channels hyperpolarize the membrane, increasing the driving force for calcium to enter the cells.…”

Voltage-Gated Potassium Channels as Regulators of Cell Death

“…The interested reader is referred to some excellent reviews [for general coverage of the topic, for instance (Blackiston et al, 2009;Urrego et al, 2014;Liu and Wang, 2019); regarding cancer (Leanza et al, 2016;Rao et al, 2015;Serrano-Novillo et al, 2019)]. Among the various voltage-gated channels, the most abundant information regarding their role in cell cycle regulation/proliferation is available about Kv1.1, Kv1.3 (for recent reviews see Pérez-Garcìa et al, 2018;Teisseyre et al, 2019), Kv1.5, Kv10.1 (Urrego et al, 2017), and Kv11.1 (He S. et al, 2020).…”

“…The Kv10.1 channel was the first with proven oncogenic potential (Pardo et al, 1999) and is overexpressed in about 70% of human tumor biopsies (Urrego et al, 2014). Kv10.1 was proposed to be crucially involved in the resorption of the primary cilium during the G2/M phase of the cell cycle, thus favoring cell cycle progression (Urrego et al, 2017). As to Kv11.1, this channel has been associated to different tumoral processes such as cell cycle progression, angiogenesis, invasiveness and metastasis formation and the channel is also overexpressed in a variety of cancer cells with respect to corresponding non-cancer tissues (He S. et al, 2020).…”

Implication of Voltage-Gated Potassium Channels in Neoplastic Cell Proliferation

“…The primary cilium consists of a microtubule-based protrusion whose basal body derives from the mother centriole. Upon cell cycle entry, the primary cilium resorbs, and the centriole is redistributed to form the microtubule-organizing center (MTOC) [98]. Transient Kv10.1 expression is transcriptionally induced during G2/M transition by the direct binding of E2F1 to the Kv10.1 promoter [99].…”

“…The channel is then located at the basal primary cilium membrane where it promotes cilium resorption. The hypothesized mechanism postulates that local membrane hyperpolarization, due to Kv10.1 activity, would lead to increased Ca 2+ influx and PIP2 dispersion from the basal cilium membrane; both events are necessary for primary cilium retraction [98]. Further examples of the importance of K + channels localization for cell cycle regulation include Kv1.3.…”