Voltage-Gated Potassium Channels as Regulators of Cell Death

Abstract

Ion channels allow the flux of specific ions across biological membranes, thereby determining ion homeostasis within the cells. Voltage-gated potassium-selective ion channels crucially contribute to the setting of the plasma membrane potential, to volume regulation and to the physiologically relevant modulation of intracellular potassium concentration. In turn, these factors affect cell cycle progression, proliferation and apoptosis. The present review summarizes our current knowledge about the involvement of various voltage-gated channels of the Kv family in the above processes and discusses the possibility of their pharmacological targeting in the context of cancer with special emphasis on Kv1.1, Kv1.3, Kv1.5, Kv2.1, Kv10.1, and Kv11.1.

Keywords: Kv-channels; cancer; cell death; cell proliferation; mitochondria.

FIGURE 1

Membrane potential changes during cell cycle progression and the role of Kv channels. During the cell cycle, the membrane potential changes constantly. A hyperpolarization occurs during the transition from G1 to S, while the membrane depolarizes during the G2/M transition. Concomitantly, calcium oscillations in the cytoplasm and volume changes orchestrate the signaling events that occur at each of the different phases of the cell cycle. Kv channels regulate these processes by setting the membrane potential, thus influencing calcium influx and cell volume, and by participating in membrane signaling complexes. Accordingly, both their expression and function changes while cells proceed through the cycle. Please refer to the text for additional details.

FIGURE 2

Kv1.3 regulates T lymphocyte proliferation: the «membrane potential model». Upon activation of T cell receptors (TCR) by antigen-presenting cells, phospholipase C (PLC) cleaves the phospholipid phosphatidylinositol 4,5-bisphosphate into diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). IP3 activates the IP3 receptor (IP3R) on the endoplasmic reticulum (ER), which releases Ca²⁺ into the cytosol. Ca²⁺ depletion from the ER lumen leads to conformational changes of the ER-resident protein STIM1, which couples the ER to the plasma membrane and activates Orai1, a calcium release-activated Ca²⁺ channel (CRAC). The following increased Ca²⁺ concentration in the cytosol activates the phosphatase Calcineurin, which dephosphorylates the Nuclear Factor of Activated T cells (NFAT). This transcription factor translocates to the nucleus and activates the transcription of interleukin-2 (IL-2), thus inducing T cell proliferation. The calcium-activated potassium channel KCa3.1 and the voltage-dependent Kv1.3 alternately open during this process and give rise to the potassium efflux that hyperpolarizes the plasma membrane, thus providing the driving force for sustained Ca²⁺ influx (Teisseyre et al., 2019). This figure was created using images from Servier Medical Art (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

FIGURE 3

Kv1.3 regulates cell proliferation independently from ion conductance: the «voltage sensor model». Changes in the plasma membrane potential, that occur during cell cycle progression or upon application of external stimuli, induce a conformational change in Kv1.3 due to its voltage-sensor domain. Because Kv1.3 interacts with other proteins in large complexes (the so-called Kv1.3 channelosome), these conformational changes translate into phosphorylation of the C-terminus of Kv1.3 and activation of pro-proliferative signal transduction cascades, including integrin and growth factor receptor (GFR) signaling. These events result in activation of Ras, which activates the Raf/Mitogen-activated protein kinase kinase (MEK)/Extracellular signal-Regulated Kinase (ERK) pathway, finally leading to proliferation mediated by different downstream transcription factors (TF) such as c-Myc (Pérez-Garcìa et al., 2018). This figure was created using images from Servier Medical Art (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

FIGURE 4

Mechanisms of Kv2.1-mediated cell death. Apoptotic stimuli such as oxidative stress lead to an increase in cytosolic free Zn²⁺ and Ca²⁺ concentrations. Zn²⁺ induces the activation of the kinases p38 and Src, which phosphorylate the intracellular pool of Kv2.1 at the residues Ser800 and Tyr124, respectively. These phosphorylations lead to insertion of Kv2.1 in the plasma membrane, an increase in the outgoing K⁺ current, apoptotic volume decrease and cell death. Plasma membrane insertion of the channel depends on interaction with the t-SNARE proteins SNAP-25 and syntaxin. The latter interacts with CamKII, activated upon an increase in Ca²⁺, favoring Kv2.1 localization to the membrane. Kv2.1 can induce apoptosis also in an ion-conducting-independent manner. Oxidative stress favors oligomerization of the protein by formation of disulfide bridges, which leads to defective endocytosis and lipid raft perturbation, resulting in activation of the Src-JNK signaling axis, finally inducing apoptosis. Please refer to the text for references and additional details. This figure was created using images from Servier Medical Art (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.

FIGURE 5

Targeting Kv10.1 and Kv11.1 in cancer. Different approaches have been employed to target Kv10.1 (on the right) and Kv11.1 (on the left) in tumor models. The most common effects that are induced by channel inhibition, activation (in the case of Kv11.1) or downregulation are summarized in the center. Please refer to the text for additional details and references. This figure was created using images from Servier Medical Art (http://smart.servier.com). Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.