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Voltage-gated potassium channels Kv1.3 are widely expressed among many cell types, both in the plasma membrane and in the inner mitochondrial membrane (mito Kv1.3 channels). The channel activity plays an important role, among others, in regulation of proliferation and apoptosis of Kv1.3 channel-expressing cells. The channel expression is significantly up-regulated upon activation of lymphocytes, microglia and macrophages. The expression of Kv1.3 channels may be significantly changed (up-regulated or down-regulated) in some cancer disorders. Inhibition of Kv1.3 channels may be beneficial in treatment of T cell-mediated autoimmune diseases (e.g. sclerosis multiplex, type I diabetes mellitus, rheumatoid arthritis, psoriasis), neuroinflammatory diseases (e.g. ischemic stroke, Parkinson’s disease, epilepsy, Alzheimer disease), ‘chronic inflammatory diseasesʼ (e.g. renal diseases, pulmonary diseases), severe cases of COVID-19, liver diseases (e.g. acute liver injury, alcoholic liver disease, hepatic fibrosis), metabolic diseases (e.g. obesity, type II diabetes mellitus) and some cancer disorders characterised by an over-expression of Kv1.3 channels (e.g. melanoma, pancreatic ductal adenocarcinoma (PDAC), multiple myeloma and B-type chronic lymphocytic leukaemia (B-CLL)). Many inhibitors of Kv1.3 channels, with distinct molecular structure and chemical properties, may putatively be applied in treatment of the diseases. However, in order to apply the channel inhibitors in medicinal practice, more research studies will have to be performed.
Department of Biophysics and Neurobiology, Medical University in Wrocław, Wrocław, Poland
Kamila Środa-Pomianek
Department of Biophysics and Neurobiology, Medical University in Wrocław, Wrocław, Poland
Anna Palko-Labuz
Department of Biophysics and Neurobiology, Medical University in Wrocław, Wrocław, Poland
Mateusz Chmielarz
Department of Microbiology, Medical University in Wrocław, Wrocław, Poland
*Address all correspondence to: andrzej.teisseyre@umw.edu.pl
1. Introduction
Voltage-gated potassium channels (Kv) are integral membrane proteins, which are selectively permeable for potassium ions and are activated upon a change of the membrane voltage. Activation of these channels enables transportation of potassium ions across the cell membrane down the electrochemical gradient. Kv channels of the Kv1.3 type, originally named as ‘nʼ (‘normalʼ) channels, were discovered in 1984 in the plasma membrane in human T lymphocytes [1] and characterised in more detail by Cahalan and co-workers 1 year later [2]. The channels are known as ‘delayed rectifier ʼ Kv channels, which activate upon membrane depolarisation and undergo a slow and complex C-type inactivation [2, 3, 4]. The C-type inactivation is defined as loss of channel’s ability to conduct ions upon a prolonged application of an activatory stimulus due to conformational changes of the channel protein, most likely of its extracellular mouth. The C-type inactivation of Kv1.3 channels is complex and contains two components: the fast and the slow one [2]. The inactivation rate depends on the extracellular concentration of potassium ions, and it is slowed when the concentration is rising from the physiological level 4.5 mM to 160 mM [2]. Activation of Kv1.3 channels in the plasma membrane provides an efflux of potassium ions out of the cell and stabilisation of the resting membrane potential [2, 3]. Kv1.3 channels are mammalian Shaker Kv channels, encoded by the KCNA3 gene [3, 4]. Active Kv1.3 channels usually exist as homotetramers formed by four identical α subunits and four intracellular regulatory β subunits [3]. However, the α subunits of Kv1.3 channels share the ability to co-assemble with α subunits of other Shaker Kv channels, but not with other Kv channel families, to form active heterotetrameric channels with biophysical and pharmacological properties different from homotetrameric Kv1.3 channels [3, 4]. Kv1.3 channels are expressed abundantly not only in human T lymphocytes but also in B lymphocytes, macrophages, fibroblasts, platelets, macrophages, osteoclasts, microglia, oligodendrocytes, brain (e.g. olfactory bulb, hippocampus, and cerebral cortex), lung, islets, thymus, spleen, lymph nodes and testis [3, 4]. Results published in 2005 provide evidence, for the first time, that Kv1.3 channels are also expressed in the inner mitochondrial membrane of normal human T lymphocytes and cancer cells: human T cell line Jurkat and CTLL-2 cells stably transfected with Kv1.3 expression vector [4, 5]. Unlike Kv1.3 channels expressed in the plasma membrane, mitochondrial Kv1.3 channels (mito Kv1.3 channels) are only slightly voltage-dependent [5]. Moreover, in contrast to what is observed for Kv1.3 channels in the plasma membrane, activation of mito Kv1.3 channels induces an influx of potassium ions inside the mitochondrial matrix, thereby depolarising the inner mitochondrial membrane [4, 5]. Mito Kv1.3 channels were also discovered in non-lymphocyte cancer cells, such as in prostate cancer PC-3 cells and breast cancer MCF-7 cells [5, 6].
Activity of Kv1.3 channels plays an important role not only in setting the cell resting membrane potential but also, among others, in cell proliferation and apoptosis [4, 7, 8, 9, 10, 11]. The first part of this chapter focuses on the role of Kv1.3 channels in regulation of proliferation and apoptosis of Kv1.3 channel-expressing cells. It is pointed out that a blockage of Kv1.3 channels in the plasma membrane inhibits Kv1.3 channel-expressing cell proliferation, whereas inhibition of mito Kv1.3 channels promotes apoptosis of cells expressing these channels, via an activation of the intracellular (mitochondrial) pathway of this process. Then, changes of Kv1.3 channel expression under physiological and pathological conditions are reviewed. Finally, it is pointed out that an inhibition of Kv1.3 channels by specific inhibitors may be beneficial in therapy of T-lymphocyte-mediated autoimmune diseases (e.g., sclerosis multiplex, type I diabetes mellitus, rheumatoid arthritis, psoriasis), chronic renal failure, asthma, obesity, type II diabetes mellitus, cognitive disabilities and some cancer disorders [4, 7, 8, 9, 10, 11]. Recently, formulated hypothesis claims that inhibition of T lymphocyte Kv1.3 channels might suppress the ‘cytokine stormʼ in severe cases of COVID-19 disease, and this could be a novel therapeutic strategy to combat the disease [12].
2. Role of activity of Kv1.3 channels in proliferation of Kv1.3 channel-expressing cells
According to the definition, cell proliferation is an increase in the number of cells due to cell growth and cell division. Cell division occurs in the last stage of the cell cycle (Figure 1).
Figure 1.
Scheme of the cell cycle.
The cell cycle contains four phases. The first three phases: G1, S and G2 taken together form the ‘interphaseʼ. The last phase, called M, is the phase of an actual cell division in the process of mitosis (Figure 1).
Activity of Kv1.3 channels is required in the G1 phase, in which the cell grows. This growth is controlled by a growth factor.
Two different models can be applied to describe the role of Kv1.3 channel in regulation of cell proliferation [4]. First of the models — the ‘membrane potential modelʼ — was first described in T lymphocytes. In these cells, Kv1.3 channel is a part of the ‘immune synapseʼ between T cell receptor (TCR) and antigen-presenting cell (APC). According to this model, Kv1.3 channels control the cell membrane potential in a cooperation with calcium-activated potassium channels K(Ca)3.1. Both channels are upregulated in activated T cells. The scheme of the cascade of events is presented in Figure 2.
Figure 2.
Scheme of the cascade of events promoting the T cell growth. Abbreviations: TCR – T cell receptor; APC – Antigen-presenting cell; PLC – Phospholipase C; DAG – Diacylglycerol; IP3 - inositol-1,4,5-triphosphate; ER – Endoplasmic reticulum; CRAC – Calcium release-activated channels; NFAT – Nuclear factor of activated T cells; IL-2 – Interleukin-2.
According to the ‘membrane potential modelʼ, an alternate opening of Kv1.3 and K(Ca)3.1 channels leads to an efflux of potassium ions out of the cell, and thereby to a hyperpolarisation of the plasma membrane. Due to the alternate potassium channel activation, the membrane potential is fluctuating around the average value. This fluctuating hyperpolarisation provides a creation of a fluctuating electrochemical ‘driving forceʼ for calcium influx through CRAC channels. Inhibition of Kv1.3 and K(Ca)3.1 channels causes a depolarisation of the plasma membrane and reduction of the ‘driving forceʼ for calcium entry. This causes an inhibition of all the downstream events, including an inhibition of IL-2 production. Lack of IL-2 inhibits the cell growth. A small cell cannot pass the checkpoint between the G1 and the S phase of the cell cycle. The cell remains arrested in the G1 phase. The proliferation is inhibited in this phase [4].
The ‘membrane potential modelʼ may have shortcomings. The results obtained with HEK 293 cells demonstrated that transfection of these cells with plasmids containing Kv1.3 channel gene stimulated cell proliferation, whereas the same operation done with family-related Kv1.5 channel gene inhibited the proliferation [4]. These results cannot be explained by the ‘membrane potential modelʼ.
Therefore, another model of the influence of Kv1.3 channel on cell proliferation known as the ‘voltage sensor modelʼ was proposed [4]. According to this model, Kv1.3 channel works as membrane voltage sensor that is sensitive to the changes in membrane potential upon sustained influx of calcium ions via the CRAC channels. The scheme of the cascade of events is shown in Figure 3.
Figure 3.
Scheme of regulation of cell proliferation by Kv1.3 channels working as the membrane ‘voltage sensor’. Abbreviations: MAPK – Mitogen-activated protein kinase; ERK – Extracellular signal-regulated kinase.
Interestingly, according to this model, a key factor necessary to promote cell proliferation is not generation of the ‘driving forceʼ for calcium ion entry but the channel opening. The proliferation is inhibited if an inhibitor prevents the channel from opening [4].
Taking into account these contradictory models, one can conclude that the mechanism of participation of Kv1.3 channel in cell proliferation is probably complex, and it may have two components: setting of cell membrane potential, which leads to generation of the ‘driving forceʼ for calcium entry, and an activation of the MAPK-ERK signalling pathway [4].
3. Role of activity of Kv1.3 channels in apoptosis of Kv1.3 channel-expressing cells
Kv1.3 channel also participates in induction of apoptosis of normal and cancer cells that express this channel [4, 5, 6, 7, 8, 9, 10, 11].
Apoptosis is a process of a programmed cell death, which occurs via two major pathways: the death receptor pathway and the mitochondrial pathway (Figure 4).
Figure 4.
Scheme of the cascade of events promoting apoptosis of a Kv1.3 channel-expressing cell.
Studies performed on Jurkat T cells showed that activity of Kv1.3 channel in the plasma membrane was up-regulated upon activation of membrane death receptors by Fas ligands [4]. The up-regulation of the channel activity occurred via caspase 8-dependent pathway. It generated a sustained efflux of potassium ions out of the cell and cell shrinkage, which is a hallmark of apoptosis [4]. It is also known that expression of mito Kv1.3 channel is required to induce the mitochondrial pathway of apoptosis by the pro-apoptotic protein Bax [4, 6]. It was shown that Bax, which is cumulated in the outer mitochondrial membrane upon apoptotic stimulation, directly and potently inhibits mito Kv1.3 channels by a peptide toxin-like mechanism [4, 6]. The EC50 value for the inhibition by Bax is about 4 nM. On the other hand, Bax does not inhibit Kv1.3 channels in the plasma membrane [6]. The inhibition of mito Kv1.3 channel is the first crucial step in the activation of the mitochondrial pathway of apoptosis (Figure 4).
Since the activation of mito Kv1.3 channel leads to a generation of an inward potassium current, inhibition of these channels would cause a hyperpolarisation of the inner mitochondrial membrane. It is known that hyperpolarisation of the inner mitochondrial membrane facilitates the production of reactive oxygen species (ROS) by mitochondria [4, 6]. Increased production of ROS activates the mitochondrial permeability transition pore (PTP) channels probably by oxidation of cysteine residues [4, 6]. Activation of the PTP leads to a loss of the mitochondrial membrane potential. Moreover, increased ROS level triggers detachment of cytochrome c probably due to oxidation of membrane lipids. Detached cytochrome c is then released from the mitochondrial space through the PTPs in the inner mitochondrial membrane [4]. Increased production of ROS, depolarization of the inner mitochondrial membrane, cytochrome c release, all these processes are hallmarks of activation of mitochondrial pathway of apoptosis.
It is well known that cancer cells often develop resistance to apoptosis. This resistance can be achieved, for example, by a down-regulation of Kv1.3 channels, including mito Kv1.3 ones, due to methylation of the promoter region of Kv1.3-encoding gene. Such a process was enhanced in patients with metastasis [4]. Alternatively, cancer cells may down-regulate pro-apoptotic Bax proteins and up-regulate anti-apoptotic Bcl proteins. A mutational inactivation-mediated deficiency of pro-apoptotic proteins Bax and Bak, which is often observed in tumour cells, can protect them from mitochondria-mediated apoptosis induced by anticancer drugs [4]. Fortunately, the pro-apoptotic effect of the Bax protein could be mimicked upon application of small-molecule organic inhibitors of Kv1.3 channels, especially ‘mitochondriotropicʼ compounds, in Kv1.3 channel-overexpressing cancer cells [4, 13, 14, 15, 16, 17] (see below).
4. Changes in expression of Kv1.3 channels under physiological and pathological conditions
It is known that resting human T lymphocytes predominantly express Kv1.3 channels (about 250 channels per cell) with a negligible contribution of calcium-activated potassium channels K(Ca)3.1 [7]. It is also known that the expression of the channels significantly increases after the cell has been activated and entered the cell cycle (Figure 1). The amount of this increase depends on the cell type. Upon an activation, human naive and central memory human T lymphocytes (TCM) slightly up-regulate Kv1.3 channels (up to ca. 300 channels per cell) and very significantly up-regulate K(Ca)3.1 channels (up to 500 channels per cell) [7]. An alternate activation of Kv1.3 and K(Ca)3.1 channels provides an effective ‘driving forceʼ for entry of calcium ions, which is necessary to promote synthesis of the cell growth factor (Figure 2). In a marked contrast, effector memory T lymphocytes (TEM) predominantly up-regulate Kv1.3 channels (up to ca. 1500 channels per cell) and only slightly up-regulate K(Ca)3.1 channels (up to ca. 50 channels per cell) [7]. In such a case, the proper ‘driving forceʼ for entry of calcium ions is provided by an activation of a bigger number of Kv1.3 channels. Under pathological conditions, in T cell-mediated autoimmune diseases, such as sclerosis multiplex, rheumatoid arthritis or type-1 diabetes, auto-antigen specific T lymphocytes are mostly terminally differentiated TEM cells, with a highly up-regulated expression of Kv1.3 channels [7].
Kv1.3 channels are also present in microglial cells and predominate (together with K(Ca)3.1 channels) in microglia, which are ‘classicallyʼ activated by lipopolysaccharide (LPS) [18]. Activity of both types of potassium channels is required in production of pro-inflammatory cytokines and nitric oxide by LPS-activated microglia [18]. Inhibition of the channels inhibits LPS-stimulated secretion of these agents [18]. Moreover, an ‘alternativeʼ activation of microglia by Interleukin-4 (IL-4), which leads to anti-inflammatory effects and tissue repair, is associated with a down-regulation of Kv1.3 channels and up-regulation of ‘inward rectifierʼ Kir2.1 channels [18].
Several studies have demonstrated an altered expression of Kv1.3 channel in tissues in case of some cancer disorders when compared to normal tissues [4, 19, 20, 21, 22]. However, no general pattern of these changes is known at the present. The changes depend on the type and the stage of the disease. In cancer tissues, these channels may be up-regulated or down-regulated. An up-regulated expression of the channel was discovered in breast or colon cancer, smooth muscle (leiomyosarcoma), skeletal muscle (alveolar rhabdomyosarcoma), lymph node cancer [4, 19, 20, 21, 22] and in mature neoplastic B cells in chronic lymphocytic leukaemia (B-CLL) [4]. It is also known that human leukaemic Jurkat T cells express both Kv1.3 channel and apamin-sensitive calcium-activated potassium channel K(Ca)2.2 [4]. Because of a high expression of Kv1.3 channels in Jurkat T cells, these cells are used as a model system in studies on biophysical and pharmacological properties of Kv1.3 channels in cancer cells. Recently, published results show that both Kv1.3 and K(Ca)3.1 channels are up-regulated in two acute lymphoblastic leukaemia cell lines: CEM and MOULT-3 [4].
In case of B-CLL, it was shown that these cancer cells express significantly more channels than normal human B lymphocytes [4]. This up-regulation may be due to a haploinsufficiency of the potassium channel regulating gene (KCNRG), which causes suppression of potassium channel expression and activity [4]. Moreover, it was shown that inhibition of B-RAF kinase by a potent anti-proliferative and pro-apoptotic compound PLX-4720 significantly reduced the expression of Kv1.3 channel in cancer B-CLL but not in normal B cells [4]. A similar reduction of Kv1.3 channel expression upon application of PLX-4270 was also observed in case of human leukaemic Jurkat T cells [4]. These results suggest that B-RAF activity is involved in the up-regulation of Kv1.3 channel in leukaemic B and T cells. This B-RAF-dependent increased expression of Kv1.3 channel in cancer cells may be related to a pro-proliferative effect on these cells [4].
On the other hand, a significantly reduced expression of the channel was observed in cancer of kidney, bladder, pancreas, lung, brain (astrocytoma, oligodendroglioma, and glioblastoma), stomach and prostate [4, 19, 20, 21, 22]. In case of prostate cancer, there was also a significant inverse correlation between expression of the channel in the epithelium of human prostate tissue and grade (p = 0.003) and stage (p = 0.001) of the tumour. Moreover, in prostate cancer, the channel expression is significantly higher in weakly metastatic cell lines: LNCaP and AT-2, than in strongly metastatic cell lines: PC3 and Mat-LyLu [4]. A significant reduction of the expression of Kv1.3 channel was also observed in case of pancreas adenocarcinoma, especially in patients with metastasis [4]. It was shown that the reduction of channel expression in the case of breast and pancreas adenocarcinoma was a consequence of methylation of the promoter region of Kv1.3-encoding gene in cancer cells. This process was enhanced in patients with metastasis [4]. There was a positive correlation between the gene methylation and the grade of the disease, but a negative correlation was obtained between the grade of disease and expression of Kv1.3 mRNA or expression of this protein [4]. Moreover, Kv1.3 gene promoter was methylated in MCF-7 breast carcinoma cell line, whereas the methylation was absent in a primary culture of normal breast cells (HMEpC) [4]. The survival distribution function showed that the gene methylation reduced the expected mean survival time for patients suffering from pancreas cancer from more than 2 years to about 1 year [4]. Recently, published data showed that the complete gene methylation was responsible for lack of expression of Kv1.3 channel in colorectal cancer cell lines: RKO, DLD-1, SW-620, HCT-116 and HT-29 [4]. On the other hand, the channel was expressed in LoVo and SW-480 cell lines, where the gene methylation occurred only partially [4]. Clinical tests showed that the gene methylation occurred in case of 76.9% (112/147) of primary colorectal cancer, whereas no methylation was detected in normal colorectal mucosa [4]. It was shown that Kv1.3 channel expression was reduced in 76.7% (23/30) of colorectal cancer patients; in almost all cases (22/23), it was due to the gene methylation [4]. The gene methylation also reduced 5-year overall survival rate (OS) of colorectal cancer patients from 80% to 64.3% [4]. Thus, both expression of Kv1.3 channel and Kv1.3 gene promoter methylation may serve as diagnostic and prognostic markers in case of breast, pancreas and colorectal cancer.
5. Inhibition of Kv1.3 channels in a medical treatment of diseases
5.1 ‘Selective immunosuppressionʼ of T cell-mediated autoimmune diseases
It is well known that in T cell-mediated autoimmune diseases, such as, for example, sclerosis multiplex, type-1 diabetes mellitus, rheumatoid arthritis or psoriasis, auto-antigen specific T lymphocytes are predominantly terminally differentiated TEM cells, which strongly and selectively up-regulate Kv1.3 channels, without any significant up-regulation of K(Ca)3.1 channels [7]. Therefore, a selective inhibition of Kv1.3 channels may selectively inhibit the proliferation, cytokine production and migration of TEM cells. On the other hand, naïve and central memory T lymphocytes (TCM) may escape from the inhibition due to a very significant up-regulation of K(Ca)3.1 channels [7]. This is an idea of the ‘selective immunosuppression ʼ, which may be a promising approach in therapy of T cell-mediated autoimmune diseases. An application of this method in a medical therapy requires an application of inhibitors, which strongly and selectively inhibit Kv1.3 channels, without significantly affecting the activity of K(Ca)3.1 channels [7]. The most promising compounds are peptide inhibitors of Kv1,3 channels, which selectively inhibit Kv1.3 channels at low nanomolar concentrations [7] (see below). The putative usefulness of application of inhibitors of Kv1.3 channels in the therapy of T cell-mediated autoimmune diseases was confirmed in studies performed on animal models of multiple sclerosis (experimental autoimmune encephalomyelitis), type-1 diabetes mellitus (experimental autoimmune diabetes), rheumatoid arthritis (pristine-induced arthritis), psoriasis (SCID-Hu mouse model) and lupus nephritis (experimental autoimmune glomerulonephritis) [7].
5.2 Neuroinflammatory disorders
5.2.1 Ischemic stroke
Ischemic stroke is the most common type of stroke, which usually occurs when the blood vessels in the neck or brain are blocked [23]. In the early stage of the stroke, there is a release of variety of cytokines, such as tumour necrosis factor alpha (TNF-α), Interleukin-1-beta (IL-1β) and Interleukininterleukin-23 (IL-23), by M1-like activated macrophages [23]. Similarly, ‘classicallyʼ (M1-like) activated microglia produce high amount of pro-inflammatory cytokines and nitric oxide impairing parenchyma in the central nervous system, which contributes to the secondary expansion of the infarct [23].
It is known that Kv1.3 channels are expressed both in macrophages and in microglia, playing an important role, among others, in cytokine production and neuronal killing [23]. Inhibition of Kv1.3 channels may inhibit the M1-like pro-inflammatory function of microglia and macrophages and switch the function of these cells to the beneficial and anti-inflammatory M2-like mode, leading to repair of damaged tissues [23]. The Kv1.3 channel inhibition-related reduction of neuroinflammation may be beneficial in improving brain damage during the stroke [23]. The most promising Kv1.3 channel inhibitors that putatively could be applied in a therapy of ischemic stroke are some peptide compounds: such as Shk, BmKTX, Margatoxin (MgTX), OSK1, Charybdotoxin (ChTX), Maurotoxin (MTX) and BF9 (Table 1).
Peptide inhibitors of Kv1.3 channels with a putative clinical application.
5.2.2 Alzheimer’s disease (AD)
AD is a progressive neurodegenerative disorder of the brain, characterised by the structural and functional loss of neurons. The main pathogenesis of AD is related to a progressive proliferation of extracellular amyloid plaques and neurofibrillary tangles inside neurons [23]. However, it is also known that neuroinflammation mediated by activated microglia, and T lymphocytes significantly contributes to the pathophysiology of the AD [23]. It is also known that Kv1.3 channels are up-regulated both in activated T lymphocytes and in ‘classicallyʼ activated microglia playing an important role in production of pro-inflammatory cytokines [7, 18]. Inhibition of the channels may inhibit microglia-mediated neuroinflammation cascades, leading to improvement of function of the brain in AD patients.
Studies performed on an animal model showed that an application of a small-molecule organic inhibitor of Kv1.3 channels, PAP-1 (see below), caused a reduction of neuroinflammation, cerebral amyloid load and improved neuronal plasticity and behavioural deficits [23]. Therefore, inhibitors of Kv1.3 channels could be attractive therapeutic agents to mitigate amyloid β-induced pro-inflammatory microglia, which are highly relevant to pathogenesis of AD. This makes these compounds candidates to become drugs for therapy of AD.
Moreover, studies performed on an animal model showed that inhibition of Kv1.3 channels exerts an anti-amnesic effect [8]. Moreover, an expression of Kv1.3 channels in hippocampal neurons, which is increased upon macrophage stimulation, results in a neuronal injury that is mitigated by inhibitors of the channels. An inhibition of Kv1.3 channels improves neuronal progenitor cell differentiation and maturation, and this could contribute to an improved self-repair of the neuronal tissue [8].
5.2.3 Epilepsy and Parkinson’s disease (PD)
Epilepsy is a chronic disease of transient brain dysfunction caused by sudden abnormal discharge of brain neurons. Potassium channels play an important role in maintaining resting membrane potential and regulating electrical excitability of neurons. In fact, many symptoms of hyperexcitability, including epilepsy, are a result of down-regulation of voltage-gated potassium channels [23]. Another important marker of epileptogenesis is an activation of microglia, leading to neuroinflammation. The activation of microglia and expression of pro-inflammatory factors are positively correlated with the progression of epilepsy in the hippocampus of patients suffering from epilepsy [23].
Another pathology of the central neuron system, which is accompanied by an activation of microglia, leading to a neuroinflammation, is Parkinson’s disease (PD). This is a degenerative disease, which involves motor deficits, including tremors, muscle rigidity, bradykinesia and impaired gait [23].
It is known that inhibition of Kv1.3 channels may inhibit the M1-like pro-inflammatory function of microglia changing the function of these cells to the beneficial and anti-inflammatory M2-like mode [18]. The channel inhibition-related reduction of neuroinflammation may be beneficial in the therapy of both above-mentioned diseases [23]. The most promising Kv1.3 channel inhibitors that putatively could be applied in a therapy of these diseases may be both some peptide blockers and organic small-molecule compounds [23] (see below). Usefulness of inhibition of Kv1.3 channels in the treatment of PD was recently confirmed in studies performed on animal models of this disease [24].
5.3 ‘Chronic inflammatory diseasesʼ
It is well known that Kv1.3 channels are over-expressed in diseases characterised by a chronical activation of the immune system, which is collectively named as ‘chronic inflammatory diseasesʼ.
Such a situation occurs among others in renal diseases, such as chronic kidney disease (CKD), renal allograft rejection and rapidly progressive glomerulonephritis [25, 26]. An over-expression of Kv1.3 channels in kidney lymphocytes promotes an excessive lymphocyte proliferation, cytokine production and activation of fibroblasts. This leads to a progression of renal fibrosis [25]. An inhibition of the channels in kidney T lymphocytes may exert beneficial immunosuppressive effects [25].
Other diseases, in which a chronic inflammation or the overstimulation of cellular immunity is responsible for the pathogenesis, are chronic respiratory diseases, such as chronic obstructive pulmonary disease, asthma, diffuse panbronchiolitis and cystic fibrosis [26]. An inhibition of Kv1.3 channels in T lymphocytes by above-mentioned compounds leads to a beneficial immunomodulation. This is accompanied by a suppression of production of pro-inflammatory cytokines, such as Interleukin-1-beta (IL-1β), tumour necrosis factor alpha (TNF-α) and Interferon gamma (IFN-γ) [26].
The Kv1.3 channel inhibitors that may exert such a beneficial effect may be nonsteroidal anti-inflammatory drugs (NSAIDs), macrolide antibiotics and calcium channel blockers (CCBs), which also inhibit Kv1.3 channels [25, 26] and statins [17] (see below).
5.4 Severe cases of COVID-19
Some patients suffering from COVID-19 disease develop fatal pneumonia with acute respiratory distress syndrome (ARDS). This is accompanied by an over-activation of leukocytes, leading to an uncontrolled release of pro-inflammatory cytokines, such as Interleukin 6 (IL-6), Interleukin 1 (IL-1), Interleukin 2 (IL-2), Interleukin 10 (IL-10), tumour necrosis factor alpha (TNF-α) and Interferon gamma (IFN-γ). This phenomenon, which is named as the ‘cytokine stormʼ, may lead to death of patients suffering from this disease.
Inhibition of Kv1.3 channels in lymphocytes, which leads to an immunosuppressive effect, may be beneficial in treatment of the ‘cytokine stormʼ in severe cases of COVID-19 [12]. Among drugs applied in treatment of COVID-19, chloroquine inhibits Kv1.3 channels in T lymphocytes and reduces the production of pro-inflammatory cytokines [12, 27]. This provides an additional pharmacological mechanism, by which chloroquine could be effective in treatment of severe cases of COVID-19 [12].
5.5 Liver diseases
5.5.1 Acute liver injury (ALI)
ALI involves severe liver injury with abnormal function of liver cells, leading to different clinical syndromes, such as clotting disorder, encephalopathy and circulatory dysfunction. ALI is associated with a high mortality rate from liver diseases. A key event in the development of liver fibrosis is an infiltration of a large number of monocyte-derived macrophages into the liver [28]. It was shown that inhibition of Kv1.3 channels expressed in macrophages by the specific inhibitor, margatoxin (MgTX), could reduce serum levels of pro-inflammatory cytokines, such as tumour necrosis factor alpha (TNF-α) or Interleukin 6 (IL-6), and reduce the infiltration of peripheral mononuclear macrophages into the liver, which could significantly protect the liver from the ALI [28]. Activity of Kv1.3 channels is essential for mononuclear cell migration; therefore, inhibition of Kv1.3 channels may reduce macrophage migration. Inhibition of the channels may also block chemotaxis of monocytes and infiltration of monocytes into the damaged brain, reducing release of neurotoxic factors by activated microglia, to alleviate brain damage [28].
5.5.2 Alcoholic liver diseases (ALDs)
The ALDs include a variety of histopathological changes, from steatosis to alcoholic steatohepatitis or even hepatocellular carcinoma [28]. Kupfer cells and macrophages are the earliest immune cells to respond to the liver response to alcohol. Therefore, macrophages and Kupfer cells play an important role in the pathogenesis of ALDs. It was shown that inhibition of Kv1.3 channels in macrophages by the specific inhibitor, margatoxin (MgTX), could reduce the secretion of macrophage pro-inflammatory factors, such as tumour necrosis factor alpha (TNF-α), Interleukin 1 (IL-1), Interleukin 20 (IL-20) and the infiltration of macrophages into the liver [28]. Thus, Kv1.3 channels could regulate macrophage function and be a new target for prevention and treatment of the ALDs [28].
5.5.3 Hepatic fibrosis
Hepatic fibrosis is related to inflammatory immune response and fibrogenic cytokines. Hepatic stellate cells (HSCs) are considered as one of the key cell types involved in the process of liver fibrosis and related pathological and clinical implications [28]. Activated HSCs produce smooth muscle actin (α-SMA), which enables myofibroblasts to proliferate. Activation of myofibroblasts could regulate the expression of pro-fibrogenic factors, such as transforming growth factor – β (TGF- β), thereby promoting the development of fibrosis [28]. It was shown that TGF- β is a key cytokine in liver fibrosis and in primary microglia. Moreover, it was shown that stimulation with TGF- β could increase the amplitude of MgTX-sensitive outward potassium current (presumably Kv1.3 current) in mouse brain microglia cell line C8-B4 [28]. Inhibition of Kv1.3 channels expressed in myofibroblasts could reduce the expression of TGF- β, thereby alleviating the development of liver fibrosis [28]. Moreover, an interperitoneal injection of MgTX in mice with liver fibrosis could exert protective effects on the liver by modulating activity of macrophages [28].
5.6 Obesity and type II diabetes mellitus (TIIDM)
It was shown that Kv1.3-deficient mice (Kv1.3−/−) unexpectedly exhibited 1000-10,000-fold lower threshold for an odour detection and increased ability to distinguish between odours [8]. In addition, Kv1.3−/− mice displayed a lean phenotype and are protected from a diet-induced obesity. Moreover, these mice are euglycemic and exhibit low blood insulin levels. Deletion of Kv1.3 channels reduced adiposity and the total body weight in a genetic model of obesity by increasing both locomotor activity and mass-specific metabolism [8].
The role of Kv1.3 channels in the adipose tissue remains a matter of controversy. Some researchers showed that white and brown adipocytes express Kv1.3 channels. An inhibition of these channels increases peripheral insulin sensitivity by promoting membrane translocation of the insulin-regulated glucose transporter GLUT4, which is responsible for the insulin-regulated glucose storage [8]. However, other scientists have not found Kv1.3 channels in the human adipose tissue or skeletal muscle, thereby questioning its role in peripheral insulin sensitivity [8]. However, an activity of Kv1.3 channels probably plays a role in central insulin sensitivity of the olfactory bulb sensing the body metabolic state. It was shown that an activation of the insulin receptor (IR) in the olfactory bulb leads to an inhibition of Kv1.3 channels in these cells via a tyrosine kinase-induced phosphorylation. This process is impaired in patients suffering from TIIDM due to a reduced activity of the IR tyrosine kinase [8].
It was shown that inhibition of Kv1.3 channels induces activity of brown adipocytes, leading to an enhanced metabolism, increased body temperature and impaired adipogenesis. This mimics effects observed in Kv1.3−/− mice. Interestingly, grapefruit (Citrus maxima), which demonstrates slimming capacity, contains various psoralens, which are inhibitors of Kv1.3 channels [8] (see below).
These findings suggest that Kv1.3 channels may be considered as putative pharmacological targets in treatment of obesity, TIIDM and related metabolic diseases [8].
5.7 Cancer disorders
Inhibition of Kv1.3 channels may be beneficial in treatment of some cancer disorders characterised by an over-expression of Kv1.3 channels, such as melanoma, pancreatic ductal adenocarcinoma (PDAC), multiple myeloma and B-type chronic lymphocytic leukaemia (B-CLL) [4, 13, 14, 15, 16, 17]. The best candidates for a putative application in medicinal therapy are lipophilic small-molecule organic inhibitors of the channels (see below). These compounds may simultaneously inhibit cancer cell proliferation — by inhibition of Kv1.3 channels in the plasma membrane and induce apoptosis of cancer cells — by inhibition of the channels in the inner mitochondrial membrane (mito Kv1.3 channels). Inhibition of mito Kv1.3 channels by these inhibitors may mimic the pro-action exerted in normal cells by the pro-apoptotic protein Bax (see above). Importantly, the apoptosis induced by the inhibitors occurs selectively in the case of cancer cells, whereas normal cells are saved. This is because of a higher expression of Kv1.3 channels (including mito Kv1.3 channels) in some cancer disorders combined with an enhanced production of reactive oxygene species (ROS) by cancer cells. Such a combination does not occur in the case of normal cells [4, 13, 14, 15, 16, 17].
6. Inhibitors of Kv1.3 channels as putative therapeutic agents
Activity of Kv1.3 channels may be inhibited by many chemically unrelated compounds: heavy-metal cations, small-molecule organic compounds and venom-isolated oligopeptides [3, 4, 5, 6, 7, 8, 9, 10]. The most potent specific inhibitors inhibit the channels at subnanomolar concentrations [3, 4, 5, 6, 7, 8, 9, 10]. However, many of the inhibitors are useless from the point of view of a putative clinical application because of low affinity, low specificity or high toxicity. Nevertheless, some inhibitors, both peptides and small-molecule organic compounds, may find a putative application in medicinal therapy.
6.1 Peptide inhibitors of the channels
Surprisingly many peptides isolated from scorpion venom and sea anemone toxins inhibit Kv1.3 channels in the picomolar to nanomolar range [8, 9, 23]. These peptides are physical Kv1.3 channel pore blockers, which bind in a vestibule at the external entrance to the channel pore [9]. Two interactions are especially important in anchoring the peptides. The first is the lysine residue, which protrudes into and occludes the channel’s selectivity filter, such as a cork in a bottle. In many peptides, this critical lysine residue, together with a neighbouring aromatic or aliphatic residue, forms a ‘functional dyadʼ required for the channel block [9].
Among sea-anemone toxin peptides the most important inhibitors of Kv1.3 channels are: ShK (isolated from Stichodactyla helianthus) and BgK (isolated from Bunodosoma granuliferum). Among scorpion venom peptides the inhibitors of Kv1.3 channels are: margatoxin (MgTX – isolated from Centruroides margaritatus), BmPO2 and BmKTX (isolated from Mesobuthus martensil), OSK1 (isolated from Orthochirus scrobiculosus), Kaliotoxin (KTX – isolated from Androtoctonus mauritanicus), Charybdotoxin (ChTX – isolated from Leiurus quinquestriatus), Maurotoxin (MTX – isolated from Scorpio maurus), Noxiustoxin (NTX – isolated from Centruroides noxius), Pi1 (isolated from Pandinus imperator) and Vm24 (isolated from Vaejovis smithi) [8, 9, 18]. In addition, there is snake toxin, BF9 (isolate from Bunganus fasciatus). All these toxins inhibit Kv1.3 channels at the concentrations from pM to nM [3, 8, 9, 23].
Peptide inhibitors of Kv1.3 channels are potent and exhibit a high specificity, especially in relation to calcium-activated potassium channels K(Ca)3.1. Therefore, these inhibitors may find clinical application in treatment of T cell-mediated autoimmune diseases and neuroinflammatory disorders (Table 1) [23].
6.2 Small-molecule organic compounds
6.2.1 Calcium channel blockers
It is well known that Kv1.3 channels are inhibited by dihydropiridines, which are blockers of voltage-gated calcium channels. Among them are: verapamil, nifedipine, diltiazem and benidipine [3, 26]. All these compounds are lipophilic, therefore, they share the ability to cross the cell membrane and act on the channel protein from the intracellular side [25, 26]. The compounds inhibit Kv1.3 channels in T lymphocytes at the concentrations up to 100 μM [26]. Calcium channel blockers, which also inhibit Kv1.3 channels in T lymphocytes, may putatively find clinical application in the treatment of ‘chronic inflammatory diseases ʼ, such as respiratory diseases or chronic kidney disease (Table 2) [25, 26].
Calcium channel blockers, which also block Kv1.3 channels, and their putative clinical application.
6.2.2 Nonsteroidal anti-inflammatory drugs (NSAIDs), macrolide antibiotics and chloroquine
Obtained data provide evidence that Kv1.3 channels expressed in T lymphocytes are also inhibited by some NSAIDs, such as diclofenac sodium, salicylate and indomethacin, and by a macrolide antibiotic clarithromycin. The compounds inhibit Kv1.3 channels at the concentrations up to 100 μM (Table 3) [25, 26].
Nonsteroidal anti-inflammatory drugs, macrolide antibiotics and chloroquine and their putative clinical application.
The mechanism of channel inhibition resembles the mechanism of action of calcium channel blockers. Inhibition of Kv1.3 channels in human T lymphocytes may contribute to immunomodulatory and anti-inflammatory effects exerted by these substances. Both the NSAIDS and clarithromycin may putatively find clinical application in treatment of ‘chronic inflammatory diseasesʼ, such as respiratory diseases or chronic kidney disease (Table 3) [25, 26].
Moreover, it was shown that an application of chloroquine, a widely used anti-malarial drug, inhibited Kv1.3 channels in murine thymocytes [27]. The effect exerted by chloroquine on the channels occurs at low micromolar concentration, and it is biphasic and voltage-dependent [27]. It may contribute to immunosuppressive effects exerted by this drug [27]. During the COVID-19 pandemic, it was shown that chloroquine applied with or without azithromycin could be effective in treatment of the ‘cytokine stormʼ in severe cases of this diseases (Table 3) [12].
6.2.3 Psoralens, their ‘mitochondriotropic’ derivatives and clofazimine
Among the most potent small-molecule organic compounds that inhibit Kv1.3 channels are psoralens [3, 4, 5, 6, 7, 8, 9, 10]. Two best known of them are: 5-(4-phenylobutoxy) psoralen (Psora-4) and 5-(4-phenoxybutoxy) psoralen (PAP-1) [3, 4, 5, 6, 7, 8, 9, 10]. Both compounds inhibit Kv1.3 channels at low nanomolar concentration, with the potency and specificity similar to that of peptide inhibitors. The psoralens could probably be applied as therapeutics for autoimmune diseases [3, 4, 5, 6, 7, 8, 9, 10]. Moreover, these compounds are lipophilic, therefore, they could be applied in treatment of some cancer disorders characterised by an over-expression of Kv1.3 channels, such as melanoma, pancreatic ductal adenocarcinoma (PDAC), multiple myeloma and B-type chronic lymphocytic leukaemia (B-CLL) [4, 13, 14, 15, 16, 17]. Another promising candidate to be applied in above-mentioned cancer disorders id N,5-bis(4-chlorophenyl)-3-(1-methylethylimino)-5H-phenazine-2-amine (clofazimine), which is applied in medicine since 1960’s as an antibiotic in a treatment of, for example, leprosy and autoimmune disorders [4]. Research studies provided evidence that clofazimine is also an inhibitor of Kv1.3 channels (Table 4) [4].
Psoralens, their ‘mitochondriotropic’ derivatives and clofazimine, with a putative clinical application.
The most promising candidates to be applied in therapy of the cancer disorders characterised by an over-expression of Kv1.3 channels are recently synthesised ‘mitochondriotropicʼ derivatives of PAP-1, whose abbreviated names are: PAPTP, PCARBTP and PCTP [4, 13, 14, 15, 16, 17]. These compounds combine high lipophilicity with a highly positive electric charge. Therefore, these compounds can preferentially accumulate in the inner mitochondrial membrane (having a strongly negative membrane potential) and inhibit mito Kv1.3 channels (Table 4) [4, 13, 14, 15, 16, 17].
The ‘mitochondriotropicʼ derivatives of PAP-1 activate the mitochondrial pathway of apoptosis in Kv1.3 channel-expressing cancer cells but not in normal cells [4, 13, 14, 15, 16, 17]. Their efficiency in a selective elimination of the cancer cells is significantly augmented when the compounds are co-applied with anti-cancer drugs, such as, for example, gemcitabine and Abraxane, in pancreatic ductal adenocarcinoma [16].
6.2.4 Natural plant-derived polycyclic compounds: flavonoids, polyphenols, chalcones and statins
It is well known that natural plant-derived flavonoids, polyphenols, chalcones and statins may exert pleiotropic effects, including those that may be related to inhibition of Kv1.3 channels. It is also known that some of compounds from above-mentioned groups inhibit Kv1.3 channels, expressed both in normal and cancer cells [4, 17, 29].
The channels are blocked by isoflavone genistein, naturally occurring polyphenol resveratrol and flavonoids: acacetin and chrysin [4]. All these compounds inhibit the channels at the concentrations up to 100 μM [4]. The most potent Kv1.3 channel inhibitors from these groups of compounds are prenyl-derivatives of flavonoid naringenin: 8-prenylo- and 6-prenylo-naringenin, isoxanthohumol and prenylated chalcones: xanthohumol, isobavachalcone and a chalconoid licochalcone A [4, 17, 29]. These compounds inhibit Kv1.3 channels at low micromolar concentrations (Table 5) [4, 29].
Plant-derived polycyclic compounds, which inhibit Kv1.3 channels, with a putative clinical application.
Another group of plant-derived inhibitors of Kv1.3 channels are statins compounds, which are known as inhibitors of cholesterol biosynthesis and drugs applied in medicinal practice to correct hypercholesterolemia. It was shown that statins: pravastatin, lovastatin, mevastatin and simvastatin are all inhibitors of Kv1.3 channels [17]. Except for pravastatin, other statins mentioned above inhibit Kv1.3 channels at low micromolar concentrations, with a potency similar to that of prenylated flavonoids and chalcones [17]. Moreover, the inhibitory effect on the channels is additive or synergistic when mevastatin is co-applied with flavonoids: 8-prenylnaringenin, 6-prenylnaringenin, acacetin, chrysin and chalcone xanthohumol, and when simvastatin is co-applied with 8-prenylnaringenin, 6-prenylnaringenin and chrysin [17].
Inhibition of Kv1.3 channels by above-mentioned compounds may be related to anti-proliferative and pro-apoptotic effects exerted by these compounds on Kv1.3 channel-expressing cancer cells [17]. The anti-cancer activity was significantly improved when the statins were co-applied with the flavonoids and xanthohumol, such as it was mentioned above [17]. This improvement was co-related with an enhanced inhibition of Kv1.3 channels [17]. Therefore, the compounds may potentially be applied in the treatment of some cancer disorders characterised by an over-expression of Kv1.3 channels, such as melanoma, pancreatic ductal adenocarcinoma (PDAC), multiple myeloma and B-type chronic lymphocytic leukaemia (B-CLL) (Table 5) [4, 13, 14, 15, 16, 17].
6.2.5 Newly designed thiophene-based inhibitors
Recently, Gubic and co-workers designed a novel structural class of small-molecule organic Kv1.3 channel inhibitors through structural optimisation of benzamide-based hit compounds and structure-activity relationship studies [30]. Structure optimisation resulted in a potent and selective Kv1.3 channel inhibitor (compound no 44) with an IC50 value of 470 nM for Kv1.3 channels expressed in Xenopus oocytes and 950 nM in Kv1.3 channel-expressing Ltk− cell line [30]. Four most potent inhibitors (compounds no 14, 37, 43 and 44) significantly inhibited proliferation of Kv1.3 channel-expressing cell line Panc-1, whereas one inhibitor (hit compound no 4) induced apoptosis of Kv1.3 channel-expressing cell line Colo357 [30]. This study demonstrates an importance of design of new, potent and selective inhibitors of Kv1.3 channels, which combine high affinity and specificity with a low toxicity.
As it was shown above, inhibition of Kv1.3 channels may be beneficial in the treatment of a wide spectrum of diseases, including autoimmune diseases, neuroinflammatory diseases, ‘chronic inflammatory diseasesʼ, severe cases of COVID-19, liver diseases, metabolic diseases and cancer disorders, which are characterised by an over-expression of Kv1.3 channels. The channels are blocked by many compounds of different molecular structures and different chemical properties. Although some of the inhibitors, such as, for example, calcium channel blockers, chloroquine, clofazimine or statins, are already applied in medicinal practice, no compound is currently applied as a therapeutic agent due to its ability to inhibit Kv1.3 channels. In order to apply various inhibitors of Kv1.3 channels in medicinal practice, more research studies are required. These studies should elucidate the role of activity of Kv1.3 channels in the pathogenesis of above-mentioned diseases, which is not fully understood yet, and importance of the channel inhibition in treatment of the diseases. Finally, clinical trials with participation of human volunteers are necessary.
Voltage-gated potassium channels Kv1.3 are widely expressed in many types of cells and play an important role in regulation of the cell function. The channel expression may significantly change both upon the cell activation and under various pathologies. Inhibition of the channels may be beneficial in the treatment in a number of well known diseases that challenge human population. Many different inhibitors of Kv1.3 channels may putatively find an application in medicinal practice. However, in order to apply the channel inhibitors as therapeutic agents, more studies will have to be performed. The most promising results are expected when inhibitors of the channels are co-applied with each other or with well known medicines already used in therapy.
The authors declare they have no conflict of interest.
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Written By
Andrzej Teisseyre, Kamila Środa-Pomianek, Anna Palko-Labuz and Mateusz Chmielarz
Submitted: 28 August 2023Reviewed: 18 October 2023Published: 11 December 2023
Open access peer-reviewed chapter - ONLINE FIRST
