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International Journal of Molecular... Jan 2022In this paper, the techniques used to study the function of mitochondrial potassium channels are critically reviewed. The majority of these techniques have been known... (Review)
Review
In this paper, the techniques used to study the function of mitochondrial potassium channels are critically reviewed. The majority of these techniques have been known for many years as a result of research on plasma membrane ion channels. Hence, in this review, we focus on the critical evaluation of techniques used in the studies of mitochondrial potassium channels, describing their advantages and limitations. Functional analysis of mitochondrial potassium channels in comparison to that of plasmalemmal channels presents additional experimental challenges. The reliability of functional studies of mitochondrial potassium channels is often affected by the need to isolate mitochondria and by functional properties of mitochondria such as respiration, metabolic activity, swelling capacity, or high electrical potential. Three types of techniques are critically evaluated: electrophysiological techniques, potassium flux measurements, and biochemical techniques related to potassium flux measurements. Finally, new possible approaches to the study of the function of mitochondrial potassium channels are presented. We hope that this review will assist researchers in selecting reliable methods for studying, e.g., the effects of drugs on mitochondrial potassium channel function. Additionally, this review should aid in the critical evaluation of the results reported in various articles on mitochondrial potassium channels.
Topics: Animals; Humans; Ion Transport; Mitochondria; Models, Biological; Potassium Channels
PubMed: 35163132
DOI: 10.3390/ijms23031210 -
Neuropharmacology Dec 2017Voltage-gated potassium channels play a key role in human physiology and pathology. Reflecting their importance, numerous channelopathies have been characterised that... (Review)
Review
Voltage-gated potassium channels play a key role in human physiology and pathology. Reflecting their importance, numerous channelopathies have been characterised that arise from mutations in these channels or from autoimmune attack on the channels. Voltage-gated potassium channels are also the target of a broad range of peptide toxins from venomous organisms, including sea anemones, scorpions, spiders, snakes and cone snails; many of these peptides bind to the channels with high potency and selectivity. In this review we describe the various classes of peptide toxins that block these channels and illustrate the broad range of three-dimensional structures that support channel blockade. The therapeutic opportunities afforded by these peptides are also highlighted. This article is part of the Special Issue entitled 'Venom-derived Peptides as Pharmacological Tools.'
Topics: Animals; Peptides; Potassium Channel Blockers; Potassium Channels, Voltage-Gated; Venoms
PubMed: 28689025
DOI: 10.1016/j.neuropharm.2017.07.002 -
Heart Rhythm Mar 2020
Topics: ERG1 Potassium Channel; Ethers; Humans; KCNQ1 Potassium Channel; Potassium Channels
PubMed: 31593778
DOI: 10.1016/j.hrthm.2019.10.009 -
Annual Review of Pharmacology and... Jan 2021Kv7 channels (Kv7.1-7.5) are voltage-gated K channels that can be modulated by five β-subunits (KCNE1-5). Kv7.1-KCNE1 channels produce the slow-delayed rectifying K... (Review)
Review
Kv7 channels (Kv7.1-7.5) are voltage-gated K channels that can be modulated by five β-subunits (KCNE1-5). Kv7.1-KCNE1 channels produce the slow-delayed rectifying K current, , which is important during the repolarization phase of the cardiac action potential. Kv7.2-7.5 are predominantly neuronally expressed and constitute the muscarinic M-current and control the resting membrane potential in neurons. Kv7.1 produces drastically different currents as a result of modulation by KCNE subunits. This flexibility allows the Kv7.1 channel to have many roles depending on location and assembly partners. The pharmacological sensitivity of Kv7.1 channels differs from that of Kv7.2-7.5 and is largely dependent upon the number of β-subunits present in the channel complex. As a result, the development of pharmaceuticals targeting Kv7.1 is problematic. This review discusses the roles and the mechanisms by which different signaling pathways affect Kv7.1 and KCNE channels and could potentially provide different ways of targeting the channel.
Topics: Action Potentials; Humans; KCNQ1 Potassium Channel; Potassium Channels, Voltage-Gated; Protein Binding; Signal Transduction
PubMed: 32667860
DOI: 10.1146/annurev-pharmtox-010919-023645 -
Journal of Neurophysiology Jul 2022Ion channel complexes typically consist of both pore-forming subunits and auxiliary subunits that do not directly conduct current but can regulate trafficking or alter...
Ion channel complexes typically consist of both pore-forming subunits and auxiliary subunits that do not directly conduct current but can regulate trafficking or alter channel properties. Isolating the role of these auxiliary subunits in neurons has proved difficult due to a lack of specific pharmacological agents and the potential for developmental compensation in constitutive knockout models. Here, we use cell-type-specific viral-mediated CRISPR/Cas9 mutagenesis to target the potassium channel auxiliary subunit Kvβ2 () in dopamine neurons in the adult mouse brain. We find that mutagenesis of reduces surface expression of Kv1.2, the primary Kv1 pore-forming subunit expressed in dopamine neurons, and shifts the voltage dependence of inactivation of potassium channel currents toward more hyperpolarized potentials. Loss of broadens the action potential waveform in spontaneously firing dopamine neurons recorded in slice, reduces the afterhyperpolarization amplitude, and increases spike timing irregularity and excitability, all of which is consistent with a reduction in potassium channel current. Similar effects were observed with mutagenesis of the pore-forming subunit Kv1.2 (). These results identify Kv1 currents as important contributors to dopamine neuron firing and demonstrate a role for Kvβ2 subunits in regulating the trafficking and gating properties of these ion channels. Furthermore, they demonstrate the utility of CRISPR-mediated mutagenesis in the study of previously difficult to isolate ion channel subunits. Here, we utilize CRISPR/Cas9-mediated mutagenesis in dopamine neurons in mice to target the gene encoding Kvβ2, an auxiliary subunit that forms a part of Kv1 channel complexes. We find that the absence of Kvβ2 alters action potential properties by reducing surface expression of pore-forming subunits and shifting the voltage dependence of channel inactivation. This work establishes a new function for Kvβ2 subunits and Kv1 complexes in regulating dopamine neuron activity.
Topics: Animals; Dopaminergic Neurons; Mice; Potassium Channels; Shaker Superfamily of Potassium Channels
PubMed: 35788155
DOI: 10.1152/jn.00194.2022 -
Cell Calcium Jul 2015Although chemotherapy is able to cure many patients with malignancies, it still also often fails. Therefore, novel approaches and targets for chemotherapeutic treatment... (Review)
Review
Although chemotherapy is able to cure many patients with malignancies, it still also often fails. Therefore, novel approaches and targets for chemotherapeutic treatment of malignancies are urgently required. Recent studies demonstrated the expression of several potassium channels in the inner mitochondrial membrane. Among them the voltage gated potassium channel Kv1.3 and the big-potassium (BK) channel were shown to directly function in cell death by serving as target for pro-apoptotic Bax and Bak proteins. Here, we discuss the role of mitochondrial potassium channel Kv1.3 (mitoKv1.3) in cell death and its potential function in treatment of solid tumors, leukemia and lymphoma. Bax and Bak inhibit mitoKv1.3 by directly binding into the pore of the channel, by a toxin-like mechanism. Inhibition of mitoKv1.3 results in an initial hyperpolarization of the inner mitochondrial membrane that triggers the production of reactive oxygen species (ROS). ROS in turn induce a release of cytochrome c from the cristae of the inner mitochondrial membrane and an activation of the permeability transition pore, resulting in opening of the intrinsic apoptotic cell death. Since mitoKv1.3 functions downstream of pro-apoptotic Bax and Bak, compounds that directly inhibit mitoKv1.3 may serve as a new class of drugs for treatment of tumors, even with an altered expression of either pro- or anti-apoptotic Bcl-2 protein family members. This was successfully proven by the in vivo treatment of mouse melanoma and ex vivo human chronic leukemia B cells with inhibitors of mitoKv1.3.
Topics: Animals; Apoptosis; Humans; Mitochondria; Neoplasms; Potassium; Potassium Channel Blockers; Potassium Channels; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species
PubMed: 25443654
DOI: 10.1016/j.ceca.2014.09.006 -
Pflugers Archiv : European Journal of... Jul 2022KCNQ channels participate in the physiology of several cell types. In neurons of the central nervous system, the primary subunits are KCNQ2, 3, and 5. Activation of...
KCNQ channels participate in the physiology of several cell types. In neurons of the central nervous system, the primary subunits are KCNQ2, 3, and 5. Activation of these channels silence the neurons, limiting action potential duration and preventing high-frequency action potential burst. Loss-of-function mutations of the KCNQ channels are associated with a wide spectrum of phenotypes characterized by hyperexcitability. Hence, pharmacological activation of these channels is an attractive strategy to treat epilepsy and other hyperexcitability conditions as are the evolution of stroke and traumatic brain injury. In this work we show that triclosan, a bactericide widely used in personal care products, activates the KCNQ3 channels but not the KCNQ2. Triclosan induces a voltage shift in the activation, increases the conductance, and slows the closing of the channel. The response is independent of PIP. Molecular docking simulations together with site-directed mutagenesis suggest that the putative binding site is in the voltage sensor domain. Our results indicate that triclosan is a new activator for KCNQ channels.
Topics: Epilepsy; Humans; KCNQ Potassium Channels; KCNQ1 Potassium Channel; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Molecular Docking Simulation; Neurotransmitter Agents; Triclosan
PubMed: 35459955
DOI: 10.1007/s00424-022-02692-w -
Journal of Medicinal Chemistry Nov 2019Rational drug design targeting ion channels is an exciting and always evolving research field. New medicinal chemistry strategies are being implemented to explore the... (Review)
Review
Rational drug design targeting ion channels is an exciting and always evolving research field. New medicinal chemistry strategies are being implemented to explore the wild chemical space and unravel the molecular basis of the ion channels modulators binding mechanisms. TASK channels belong to the two-pore domain potassium channel family and are modulated by extracellular acidosis. They are extensively distributed along the cardiovascular and central nervous systems, and their expression is up- and downregulated in different cancer types, which makes them an attractive therapeutic target. However, TASK channels remain unexplored, and drugs designed to target these channels are poorly selective. Here, we review TASK channels properties and their known blockers and activators, considering the new challenges in ion channels drug design and focusing on the implementation of computational methodologies in the drug discovery process.
Topics: Animals; Drug Design; Drug Discovery; Humans; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Tandem Pore Domain
PubMed: 31260312
DOI: 10.1021/acs.jmedchem.9b00248 -
ELife Mar 2017Electron cryo-microscopy has revealed the three-dimensional structure of a potassium channel that has a central role in regulating the release of insulin from the...
Electron cryo-microscopy has revealed the three-dimensional structure of a potassium channel that has a central role in regulating the release of insulin from the pancreas.
Topics: Adenosine Triphosphate; Cryoelectron Microscopy; Insulin; Ions; Potassium Channels, Inwardly Rectifying; Sulfonylurea Receptors
PubMed: 28276322
DOI: 10.7554/eLife.25159 -
Arteriosclerosis, Thrombosis, and... Sep 2014Perivascular adipose tissue has been recognized unequivocally as a major player in the pathology of metabolic and cardiovascular diseases. Through its production of... (Review)
Review
Perivascular adipose tissue has been recognized unequivocally as a major player in the pathology of metabolic and cardiovascular diseases. Through its production of adipokines and the release of other thus far unidentified factors, this recently discovered adipose tissue modulates vascular regulation and the myogenic response. After the discovery of its ability to diminish the vessel's response to vasoconstrictors, a new paradigm established adipose-derived relaxing factor (ADRF) as a paracrine smooth muscle cells' potassium channel opener that could potentially help combat vascular dysfunction. This review will discuss the role of ADRF in vascular dysfunction in obesity and hypertension, the different potassium channels that can be activated by this factor, and describes new pharmacological tools that can mimic the ADRF effect and thus can be beneficial against vascular dysfunction in cardiovascular disease.
Topics: Adipokines; Adipose Tissue; Animals; Biological Factors; Blood Vessels; Cardiovascular Diseases; Endothelium, Vascular; Humans; Hypertension; KCNQ Potassium Channels; Muscle Contraction; Muscle, Smooth, Vascular; Obesity; Potassium Channel Blockers; Potassium Channels; Vasoconstrictor Agents
PubMed: 25012133
DOI: 10.1161/ATVBAHA.114.303032