Margatoxin MgTx , an inhibitor of Kv1. This was proposed to be ascribable to the effect of MgTx on cell cycle progression Jang et al. In addition to cancer, Kv1. Figure 2. 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. As to Kv1. However, expression of Kv1.
In accordance, silencing Kv1. Altogether, a conclusive general picture regarding the involvement of Kv1. These proteins can apparently promote proliferation also independently of their ion-conducting properties, but in function of the presence of two phosphorylation sites at the C-terminus of the channels Figure 3 ; see e.
Only sporadic studies addressed the role of other Kv1. Figure 3. Changes in the plasma membrane potential, that occur during cell cycle progression or upon application of external stimuli, induce a conformational change in Kv1. Because Kv1. Among channels of the Kv2. Silencing of the Kv2. The specific blocker of Kv2. Another study showed that Ts15, a toxin from Tityus serrulatus , inhibited proliferation of central memory T cells, where Kv2.
In contrast, downregulation of Kv2. To our knowledge, Ts15 and Hanatoxin-1 have not been explored in the context of cancer in other studies. It has been reported that block of Kv3. On the other hand, a recent report elucidated the mechanism by which Kv3. Kv4 channels have been characterized mainly in the context of neuronal function, but a recent work identified peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 Pin1 , a prolyl isomerase that promotes cancer cell proliferation, as an interactor of Kv4.
The importance of this interaction was underlined in the context of cognitive flexibility, but not of cancer so far. A recent work highlighted Kv7. Interestingly, Tamoxifen, often used against breast cancer, inhibits Kv7. However, the role of this effect in the context of breast or other cancers has not been explored. In addition to the above-mentioned channels, work from different labs on Kv The Kv As to Kv Indeed, implications of Kv Recent results revealed that in esophaegal squamous cell carcinoma, Kv In bladder cancer, miR was found to regulate Kv Using a miR inhibitor, Kv Similar effects on proliferation, migration and apoptosis were obtained in osteosarcoma cells by inhibition of Kv Strikingly, most of the above-mentioned channels are intimately linked not only to proliferation, but also to the regulation of apoptosis Szabo et al.
Here, we discuss the role of Kv channels in cell death. In particular, the channel was shown to be inhibited within a few minutes following apoptosis induction by CD95 Szabo et al. This post-translational modification was shown to inhibit Kv1. On the other hand, in a still early phase of apoptosis, the channel was shown to be activated by apoptotic stimuli and to contribute to the so-called apoptotic volume decrease in lymphocytes Storey et al.
Further work is required to understand the importance of these findings, since Margatoxin, an inhibitor of Kv1. Nonetheless, using genetic models or silencing of Kv1.
This finding might explain why the channel is found less expressed in several types of cancer tissue samples at advanced stage with respect to healthy tissues Serrano-Novillo et al. Similar findings were reported for Kv1.
As a follow up of these findings, Kv1. In addition to Kv1. For example, enhanced Kv1. In contrast, downregulation of specifically Kv1. In agreement, Margatoxin reduced cell death in this system, where Kv1. Thus, also in the case of Kv1. Since Kv1. Indeed, the role of Kv1. Bonnet and colleagues correlated low Kv1. In particular, these authors observed that metabolic shift toward oxidative phosphorylation and the consequent reactive oxygen species release from mitochondria activates plasma membrane Kv1.
On the other hand, a more recent work showed that silencing Kv1. Pharmacological inhibition of Kv1. In another study however, silencing of Kv1. In a recent investigation, inhibition of Kv1. Similarly, DPO-1 reduced hydrogen peroxide-evoked endothelial cell apoptosis Chen et al. In summary, while considerable experimental work links plasma membrane Kv channels to apoptosis, contrasting findings about their expression level in cancer cells as well as their involvement in the regulation of the apoptotic pathway deserves attention.
The Kv2. An involvement of Kv2. The importance of Kv2. They demonstrated that the expression of dominant-negative Kv2.
Accordingly, the transient expression of functional Kv2. The same group identified compound 48F10 that inhibits Kv2. Upon application of apoptotic stimuli, an increased trafficking of Kv2.
The de novo insertion of Kv2. The interaction of Kv2. Calcium thus emerges as a regulator of the potassium current surge at the onset of neuronal apoptosis McCord and Aizenman, Interestingly, targeting the Kv2. Figure 4. Mechanisms of Kv2. These phosphorylations lead to insertion of Kv2.
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. Membrane trafficking of Kv2. For example, activation of the mitogen-activated protein MAP kinase p38 is necessary for the induction of neuronal apoptosis after oxidative injury.
By phosphorylating a serine residue at the C-terminal of the channel protein S , active p38 leads to membrane insertion of Kv2. Src kinase is responsible for phosphorylation of the channel at Y, enhancing the Kv2. Phosphorylation at S and Y mutually co-regulate each other, with P-Y facilitating the action of p38 on S and vice versa He et al.
Additionally, serum deprivation, which induces apoptosis of cortical neurons in a model of excitotoxicity, leads to N-Methyl-d-aspartate NMDA receptor activation and enhanced plasma membrane expression of Kv2. It was further shown that activation of Protein Kinase A PKA following an increase in cyclic AMP protects cerebellar granular neurons from cell death induced by potassium-low and serum-free medium Jiao et al.
In this study, PKA activation decreased the Kv2. Cleavage of Kv2. Liu et al. The complex interplay between Kv2. In many central nervous system CNS disorders, microglia are involved in promoting neurodegeneration.
The mechanisms described above partly account for the neurodegenerative effect of microglia: Knoch et al. In addition to neurodegeneration, p38 activation and apoptosis induction play a relevant role also in hepatitis virus C HVC infections. Interestingly, also expression of NS5A1b in neurons is protective as it inhibits Kv2.
Human immunodeficiency virus 1 HIV-1 is involved in neuronal apoptosis as well. Its envelope glycoprotein gp has been associated to the pathogenesis of HIVassociated neurodegenerative disorders by acting on Kv2.
In hippocampal neurons, gp was shown to increase Kv2. This addictive drug exhibits strong neurotoxicity, inducing apoptosis via activation of p38, upregulation of Kv2. It has been shown that carbon monoxide CO protects neurons from oxidant-induced apoptosis by inhibition of Kv2.
In fact, the hypoxic environment of tumors favors the constitutive expression of heme oxygenase 1 HO-1 , which catalyzes heme and releases CO as a byproduct, finally leading to Kv2. Interestingly, Donepezil, an acetylcholinesterase inhibitor used in AD, was shown to inhibit Kv2. Direct oxidation of Kv2. Cotella et al. These oligomers, although exhibiting decreased open probability, triggered apoptotic cell death. Cholesterol, by stabilizing lipid rafts, could revert the onset of apoptosis Wu X.
Accordingly, transgenic mice harboring a non-oxidizable Kv2. Importantly, the results from these experiments were mimicked by treatment of control mice with Dasatinib, a Src kinase inhibitor. The findings of these studies suggest that under oxidizing conditions, such as during aging or neurodegenerative diseases, Kv2.
In addition to its well-established role in neuronal apoptosis, Kv2. In these cells, Kv2. Additionally, the small-molecule inhibitors of Kv2. Similarly to Kv2. Similarly, Kv3. Interestingly, the authors of this study suggest an involvement of mitochondrial Kv3. Regarding Kv7 channels, their inhibition was demonstrated to trigger spiral ganglion neuron death, possibly underlying the autosomal dominant version of progressive hearing loss associated with Kv7. On the other hand, activation of Kv7.
Interestingly, blockade of Kv7 channels by amyloid precursor proteins may regulate neuronal excitation and possibly cell death Lee et al. While Kv10 and Kv12 channels are expressed primarily in the central nervous system, Kv11 is present also in the heart, where it regulates the termination of the cardiac action potential, and in smooth muscle tissues Barros et al.
Ion channels belonging to the EAG family have been intensively studied in the context of cancer. Their expression is frequently high in a wide range of tumor types, while lacking in the corresponding non-tumoral tissues He S. Although, to our knowledge, in-depth mechanistic studies regarding the involvement of EAG channels in the regulation of apoptosis are missing, different studies suggest that channel activity may either promote or block the induction of cell death depending on the cell type and the environment.
Studies in which targeting Kv10 or Kv11 channels was exploited to induce tumor cell death will be analyzed more in detail below. Although several types of Kv channels are linked to either altered proliferation, or to apoptosis induction, concrete steps toward cancer treatment have been obtained only in few cases.
This situation is most probably due to our limitation of having promiscuous pharmacological inhibitors as tools to modulate the function of these channels. Nonetheless, the use of toxins, small molecules and specific antibodies is emerging as promising strategy for recent review see e. Intratumoral injection of Margatoxin, a Kv1. Two toxins, acting on Kv1. A disadvantage of these toxins, however, is their inability to cross the blood brain barrier and to act on intracellular potassium channels.
Instead, recent evidence indicates that mitochondrial ion channels can be of importance in fighting cancer. For example, pharmacological inhibition of the mitochondria-located counterpart of Kv1.
Different strategies have been exploited to specifically target Kv Given the structural similarity between the potassium channel superfamily, specific blockers are difficult to obtain, therefore some of the research has focused on antibody-based or genetic strategies. For example, a monoclonal antibody raised against Kv Additionally, specific small antibody fragments targeting the extracellular pore domain of Kv These constructs sensitized breast cancer cells to chemotherapeutics they were otherwise resistant to Hartung and Pardo , or directly induced cell death in prostate and pancreatic cancer cells when fused to a TRAIL variant with enhanced pro-apoptotic activity Hartung et al.
This antibody-based strategy was proven efficacious also in vivo Hartung and Pardo, The specificity of this treatment relies on the enhanced expression of Kv Similarly, treating the human osteosarcoma cell line MG or mice bearing an osteosarcoma xenograft with adenoviral vectors that simultaneously knockdown Kv Figure 5. Targeting Kv Different approaches have been employed to target Kv The most common effects that are induced by channel inhibition, activation in the case of Kv Please refer to the text for additional details and references.
Another strategy for the treatment of cancer that has gained increased interest in recent years is drug repositioning using clinically safe drugs already exploited for some other disease. Regarding Kv This compound was associated with a reduced cancer mortality by sensitizing cells to chemotherapy Ellegaard et al.
The same drug was used to target proliferation and viability of hepatocellular carcinoma cells in vitro and in an in vivo mouse model, where it decreased Kv Furthermore, Astemizole increased the anti-proliferative effects of calcitriol on breast cancer both in vitro and in vivo by acting also on Kv Knockdown of Kv Astemizole thus represents a valid candidate for drug repositioning Figure 5. Natural compounds are also promising tools.
Very recently, the natural compound Procyanidin B1 was identified as a rather specific inhibitor of Kv In addition, the only Kv Although representing an interesting target for cancer therapy, Kv Nonetheless, some studies achieved promising results with channel activators or blockers Figure 5.
For example, the incidental administration of FDA-approved drugs with proven inhibitory activity on Kv These drugs did not have any adverse side-effect on cardiac activity and include Phenytoin, Haloperidol, Fluoxetine, Tamoxifen, Amitriptyline, and Ketoconazole Pointer et al.
In acute lymphoblastic leukemia ALL cells, the Kv E significantly reduced tumor progression and improved survival also in vivo Pillozzi et al. Simultaneous activation of the calcium- and voltage-dependent potassium channel KCa3. Erythomycin was also shown to increase the cytotoxic effect of paclitaxel, vincristine and hydroxy-camptothecin on different cancer cell lines that express Kv Similarly, the gastroprokinetic drug cisapride was shown to inhibit Kv Further, inhibition of Kv The effect of doxazosin was mimicked by siRNA-mediated knockdown of the channel Bishopric et al.
Interestingly, two main isoforms are known for Kv While Kv This peculiarity has been exploited by Gasparoli et al. CD caused apoptosis and growth arrest of leukemic cells in vitro and showed strong antileukemic effects in vivo Gasparoli et al. The higher expression of Kv They engineered polyethylene-glycol gold nanoparticles fused to an anti-Kv In addition, the antibiotic clarithromycin, whose mammalian targets include Kv Finally, to avoid cardiac side-effects, Gentile and co-workers proposed an opposite approach to Kv They used a small-molecule activator of the channel, NS, to achieve in vivo inhibition of tumor growth of triple-negative breast cancer Fukushiro-Lopes et al.
In their model, prolonged activation of the channel leads to hyperpolarization, increase in ROS production, DNA damage, activation of a senescence program and arrest of proliferation. Importantly, NS did not cause cardiac arrythmias. However, possible side effects of NS, other than cardiotoxicity, have not been investigated in a systematic way in vivo. In addition, toxins might offer a way of intervention: CsEKerg1 toxin, from the Centruroides sculpturatus scorpion, inhibits Kv Collectively, these studies demonstrate that several ion channels are attractive targets for cancer therapy and regulation of the immune response.
As outlined in the present review, many channels share at least some functional aspects with other channels and it might be necessary to define combinations of drugs acting on ion channels for successful tumor treatment. In addition, many channels are expressed in several cell types and it remains to be defined whether channels can be selectively targeted in tumor cells.
Nevertheless, the functions of many ion channels remain unknown, and their structure-function relationships are still undefined. Despite being very small structures, ion channels have large functions; they control the beating of a heart, the perception of sound or sight, or storage of a memory.
Ultimately, these biological processes depend not on a single ion channel, but on all the ion channels in a cell and tissue network functioning in a coordinated manner. How this happens will continue to capture our imagination and attention for decades to come.
Ackerman, M. Nature Medicine 10 , — Doyle, D. Science , 69—77 Hille, B. Ionic Channels of Excitable Membranes. Sunderland, MA: Sinauer Associates, Hodgkin, A. Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. Journal of Physiology , — a. The components of membrane conductance in the giant axon of Loligo.
Journal of Physiology , — b. The dual effect of membrane potential on sodium conductance in the giant axon of Loligo.
Journal of Physiology , — c. A quantitative description of membrane current and its application to conduction and excitation in nerve. Journal of Physiology , — d. Propagation of electrical signals along giant nerve fibers. Movement of sodium and potassium ions during nervous activity. Measurement of current-voltage relations in the membrane of the giant axon of Loligo.
Journal of Physiology , —48 Lai, H. The distribution and targeting of neuronal voltage-gated ion channels. Nature Reviews Neuroscience 7, —62 Cell Signaling. Ion Channel. Cell Adhesion and Cell Communication. Aging and Cell Division. Endosomes in Plants. Ephs, Ephrins, and Bidirectional Signaling. Ion Channels and Excitable Cells. Signal Transduction by Adhesion Receptors. Rasband, Ph. Citation: Rasband, M. Nature Education 3 9 Ion channels control or regulate diverse physiological activities in our body.
Aa Aa Aa. Ionic Theory of Action Potential Propagation. In general, action potentials occur in all excitable cells. The main question they sought to address was, how does an electrical signal propagate in a cell from one location to another? To answer this question they used the squid giant axon, since it offered several experimental advantages. It permitted them 1. From their experiments, Hodgkin and Huxley were able to show that differences in ion concentrations exist between the inside and outside of cells, that the properties of the action potential depend on these ionic concentrations, and that transient changes in the permeability of the cell membrane to these ions accounts for the propagation of the action potential along the squid giant axon.
These conductances had specific properties, including selectivity for one ion over another, distinct kinetics. For their work, Hodgkin and Huxley were awarded the Nobel prize in physiology and medicine in To this day their work stands as one of the best examples of how scientists can use mathematics to provide insights into complicated biological systems.
What Is an Ion Channel? How Do Ion Channels Work? Figure 3: Amino acid sequences. The amino-acid sequences from a range of ion channels center show remarkable similarity in the region of the selectivity filter.
Figure 4: Channelopathies. References and Recommended Reading Ackerman, M. Article History Close. Share Cancel. Revoke Cancel. Keywords Keywords for this Article. Save Cancel. Flag Inappropriate The Content is: Objectionable. Flag Content Cancel. Email your Friend.
The pore then closes to allow for control of diffusion across the membrane once potassium ions are flowing the the filter. There are many types of ion channels, but this paper will be focusing on potassium channels. The human genome contains over 90 genes that encode for potassium channels.
There are four main types of potassium channels which are as followed: calcium activated, inwardly rectifying, tandem pore domain, and voltage-gated.
The differences between these types are mainly with how the gate receives its signal, whereas the structure of these channels is similar. A general structure for potassium channels can be seen below in Figure 2. Figure 2. General structure of potassium channels showing the two conformations of the closed state a and b of KcsA vs. Also, the transmembrane TM domain and the cytoplasmic domain of highlighted here. The gray rectangle represents the molecule would be located in the membrane.
All three molecules are from bacteria, but have different gating dependence. KcsA is pH dependent, whereas MthK is voltage dependent. Potassium is an alkali metal with a valence electron configuration of n s1 and contributes only one element to the molecular orbital band.
There are some common trends that can be found from the periodic table, and there are specific ones that are for alkali metals. Oxidation becomes more favorable going down the group because the enthalpies of sublimation and ionization decrease. Group 1 element ions are hard Lewis acids and mainly form complexes with hard donors like O and N. This paper will be focusing on KcsA, a potassium channel from Streptomyces lividans , which contains two domains.
The first being the transmembrane portion, which contains residues. This will be discussed in detail below. The second domain is a cytoplasmic domain that contains about 40 residues. The cytoplasmic domain contributes to the stability of the closed state. This is concluded based on data that shows a decrease in efficiency of channel folding and assembly and thermal stability being affect when the cytoplasmic domain is removed from the crystal structure.
A suggested function of the domain is that it may serve as a receptor for an unidentified plasmic activator protein or ligand, but others argue that there is no significant effect on the permeation path for the ion.
The structure does not yet contain orientation of any side chains, but the arrangement of the helices suggest electrostatic interactions in the subunit. Figure 3. The transmembrane domain. Each subunit is colored differently and the potassium ions are purple. PDB 1BL8. The selectivity for potassium ions relies heavily on the structure of the potassium channel selectivity filter.
The coordination environment of the channel has selective ligands that bind specifically to potassium ions. The subunits contain two alpha helices where one faces the central pore, inner helix, and one faces the lipid membrane, otherwise known as the outer helix.
The four inner helices are structured in a way where they come together near the intracellular surface. Both the intra- and extracellular entryways are negatively charged by acidic amino acids. This allows for a higher concentration of cations near the membrane and less anions because of the opposing charges.
Figure 4. Potassium channel KcsA structure from Streptomyces lividans with key structural components labeled. The main aspects to note are the pore, cavity, and selectivity filter SF. These are the parts of the channel where potassium ions travel through. First, the ion flows through the pore and enters the cavity hydrated when the pore is open. Then a potassium ion is dehydrated and selected to travel through the SF where it will then enter the cell.
Note that only two subunits are shown in this image for easier visualization. PBD 1K4C. The pore region was first identified with pore-blocking scorpion toxins. They interact with amino acids at the entrance of the pore causing blocking and dysfunction. The pore is where the potassium ion enters, where then it is transferred to the central cavity, as seen in Figure 4.
During this time the potassium ion stays hydrated. The channels opens when there is a change in membrane potential, allowing a influx of potassium ions into the cavity filter. Once selective binding occurs in the selectivity filter, the potential drops across the membrane, thus closing the pore. There needs to be a lower electrostatic barrier so the energetic cost of dehydration is compensated due to the large energy barrier for ion permeation dielectric barrier.
Thus, the water filled cavity allows for an energetically favourable environment. Figure 5. The full coordination is not shown here for easier visualization.
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