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Molecules (Basel, Switzerland) Jan 2022Mitochondrial potassium channels control potassium influx into the mitochondrial matrix and thus regulate mitochondrial membrane potential, volume, respiration, and... (Review)
Review
Mitochondrial potassium channels control potassium influx into the mitochondrial matrix and thus regulate mitochondrial membrane potential, volume, respiration, and synthesis of reactive oxygen species (ROS). It has been found that pharmacological activation of mitochondrial potassium channels during ischemia/reperfusion (I/R) injury activates cytoprotective mechanisms resulting in increased cell survival. In cancer cells, the inhibition of these channels leads to increased cell death. Therefore, mitochondrial potassium channels are intriguing targets for the development of new pharmacological strategies. In most cases, however, the substances that modulate the mitochondrial potassium channels have a few alternative targets in the cell. This may result in unexpected or unwanted effects induced by these compounds. In our review, we briefly present the various classes of mitochondrial potassium (mitoK) channels and describe the chemical compounds that modulate their activity. We also describe examples of the multidirectional activity of the activators and inhibitors of mitochondrial potassium channels.
Topics: Adenosine Triphosphate; Animals; Calcium; Humans; Ion Channel Gating; Mitochondrial Membrane Transport Proteins; Potassium; Potassium Channel Blockers; Potassium Channels
PubMed: 35011530
DOI: 10.3390/molecules27010299 -
The Journal of Physiology Jun 2015The most essential properties of ion channels for their physiologically relevant functions are ion-selective permeation and gating. Among the channel species, the... (Review)
Review
The most essential properties of ion channels for their physiologically relevant functions are ion-selective permeation and gating. Among the channel species, the potassium channel is primordial and the most ubiquitous in the biological world, and knowledge of this channel underlies the understanding of features of other ion channels. The strategy applied to studying channels changed dramatically after the crystal structure of the potassium channel was resolved. Given the abundant structural information available, we exploited the bacterial KcsA potassium channel as a simple model channel. In the postcrystal age, there are two effective frameworks with which to decipher the functional codes present in the channel structure, namely reconstitution and re-animation. Complex channel proteins are decomposed into essential functional components, and well-examined parts are rebuilt for integrating channel function in the membrane (reconstitution). Permeation and gating are dynamic operations, and one imagines the active channel by breathing life into the 'frozen' crystal (re-animation). Capturing the motion of channels at the single-molecule level is necessary to characterize the behaviour of functioning channels. Advanced techniques, including diffracted X-ray tracking, lipid bilayer methods and high-speed atomic force microscopy, have been used. Here, I present dynamic pictures of the KcsA potassium channel from the submolecular conformational changes to the supramolecular collective behaviour of channels in the membrane. These results form an integrated picture of the active channel and offer insights into the processes underlying the physiological function of the channel in the cell membrane.
Topics: Cell Membrane; Humans; Ion Channel Gating; Potassium Channels
PubMed: 25833254
DOI: 10.1113/JP270025 -
ELife May 2013The structure of a complex containing a toxin bound to a potassium ion channel has been solved for the first time, revealing how scorpions have designed toxins that can...
The structure of a complex containing a toxin bound to a potassium ion channel has been solved for the first time, revealing how scorpions have designed toxins that can recognize and target the filter that controls the movement of potassium ions through these channels.
Topics: Potassium Channels; Toxins, Biological
PubMed: 23705072
DOI: 10.7554/eLife.00873 -
Physiology (Bethesda, Md.) Jan 2023Potassium channels are widespread over all kingdoms and play an important role in the maintenance of cellular ionic homeostasis. Kv1.3 is a voltage-gated potassium... (Review)
Review
Potassium channels are widespread over all kingdoms and play an important role in the maintenance of cellular ionic homeostasis. Kv1.3 is a voltage-gated potassium channel of the Shaker family with a wide tissue expression and a well-defined pharmacology. In recent decades, experiments mainly based on pharmacological modulation of Kv1.3 have highlighted its crucial contribution to different fundamental processes such as regulation of proliferation, apoptosis, and metabolism. These findings link channel function to various pathologies ranging from autoimmune diseases to obesity and cancer. In the present review, we briefly summarize studies employing Kv1.3 knockout animal models to confirm such roles and discuss the findings in comparison to the results obtained by pharmacological modulation of Kv1.3 in various pathophysiological settings. We also underline how these studies contributed to our understanding of channel function in vivo and propose possible future directions.
Topics: Animals; Potassium Channels, Voltage-Gated; Potassium Channels
PubMed: 35998249
DOI: 10.1152/physiol.00010.2022 -
Current Topics in Membranes 2014At normal body temperature, the two-pore potassium channels TREK-1 (K2P2.1/KCNK2), TREK-2 (K2P10.1/KCNK10), and TRAAK (K2P4.1/KCNK2) regulate cellular excitability by... (Review)
Review
At normal body temperature, the two-pore potassium channels TREK-1 (K2P2.1/KCNK2), TREK-2 (K2P10.1/KCNK10), and TRAAK (K2P4.1/KCNK2) regulate cellular excitability by providing voltage-independent leak of potassium. Heat dramatically potentiates K2P channel activity and further affects excitation. This review focuses on the current understanding of the physiological role of heat-activated K2P current, and discusses the molecular mechanism of temperature gating in TREK-1, TREK-2, and TRAAK.
Topics: Animals; Ion Channel Gating; Mechanical Phenomena; Potassium Channels; Thermosensing
PubMed: 25366235
DOI: 10.1016/B978-0-12-800181-3.00005-1 -
Clinical EEG and Neuroscience Mar 2024Impairments in gamma-aminobutyric acid (GABAergic) interneuron function lead to gamma power abnormalities and are thought to underlie symptoms in people with...
Impairments in gamma-aminobutyric acid (GABAergic) interneuron function lead to gamma power abnormalities and are thought to underlie symptoms in people with schizophrenia. Voltage-gated potassium 3.1 (Kv3.1) and 3.2 (Kv3.2) channels on GABAergic interneurons are critical to the generation of gamma oscillations suggesting that targeting Kv3.1/3.2 could augment GABAergic function and modulate gamma oscillation generation. Here, we studied the effect of a novel potassium Kv3.1/3.2 channel modulator, AUT00206, on resting state frontal gamma power in people with schizophrenia. We found a significant positive correlation between frontal resting gamma (35-45 Hz) power ( = 22, = 0.613, < .002) and positive and negative syndrome scale (PANSS) positive symptom severity. We also found a significant reduction in frontal gamma power ( = 3.635, = .003) from baseline in patients who received AUT00206. This provides initial evidence that the Kv3.1/3.2 potassium channel modulator, AUT00206, may address gamma oscillation abnormalities in schizophrenia.
Topics: Humans; Potassium Channels; Schizophrenia; Electroencephalography; Interneurons; Potassium
PubMed: 36591873
DOI: 10.1177/15500594221148643 -
European Journal of Medicinal Chemistry Nov 2023Voltage-gated potassium channel K1.3 inhibitors have been shown to be effective in preventing T-cell proliferation and activation by affecting intracellular Ca...
Voltage-gated potassium channel K1.3 inhibitors have been shown to be effective in preventing T-cell proliferation and activation by affecting intracellular Ca homeostasis. Here, we present the structure-activity relationship, K1.3 inhibition, and immunosuppressive effects of new thiophene-based K1.3 inhibitors with nanomolar potency on K current in T-lymphocytes and K1.3 inhibition on Ltk cells. The new K1.3 inhibitor trans-18 inhibited K1.3 -mediated current in phytohemagglutinin (PHA)-activated T-lymphocytes with an IC value of 26.1 nM and in mammalian Ltk cells with an IC value of 230 nM. The K1.3 inhibitor trans-18 also had nanomolar potency against K1.3 in Xenopus laevis oocytes (IC = 136 nM). The novel thiophene-based K1.3 inhibitors impaired intracellular Ca signaling as well as T-cell activation, proliferation, and colony formation.
Topics: Animals; Mammals; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Structure-Activity Relationship; T-Lymphocytes; Thiophenes; Immunosuppressive Agents
PubMed: 37454520
DOI: 10.1016/j.ejmech.2023.115561 -
FEBS Letters May 2010Mitochondrial potassium channels play an important role in cytoprotection. Potassium channels in the inner mitochondrial membrane are modulated by inhibitors and... (Review)
Review
Mitochondrial potassium channels play an important role in cytoprotection. Potassium channels in the inner mitochondrial membrane are modulated by inhibitors and activators (potassium channel openers) previously described for plasma membrane potassium channels. The majority of mitochondrial potassium channel modulators exhibit a broad spectrum of off-target effects. These include uncoupling properties, inhibition of the respiratory chain and effects on cellular calcium homeostasis. Therefore, the rational application of channel inhibitors or activators is crucial to understanding the cellular consequences of mitochondrial channel inhibition or activation. Moreover, understanding their side-effects should facilitate the design of a specific mitochondrial channel opener with cytoprotective properties. In this review, we discuss the complex interactions of potassium channel inhibitors and activators with cellular structures.
Topics: Adenosine Triphosphate; Animals; Homeostasis; Humans; Ion Channel Gating; Mitochondria; Potassium Channel Blockers; Potassium Channels
PubMed: 20178786
DOI: 10.1016/j.febslet.2010.02.048 -
FEBS Letters Nov 2003The atomic structures of K+ channels have added a new dimension to our understanding of K+ channel function. I will briefly review how structures have influenced our... (Review)
Review
The atomic structures of K+ channels have added a new dimension to our understanding of K+ channel function. I will briefly review how structures have influenced our views on ion conduction, gating of the pore, and voltage sensing.
Topics: Amino Acid Sequence; Bacterial Proteins; Ion Channel Gating; Ion Transport; Membrane Potentials; Models, Molecular; Molecular Sequence Data; Potassium Channels; Protein Conformation; Sequence Homology, Amino Acid
PubMed: 14630320
DOI: 10.1016/s0014-5793(03)01104-9 -
Genome Biology 2000Potassium channels, tetrameric integral membrane proteins that form aqueous pores through which K+ can flow, are found in virtually all organisms; the genomes of humans,... (Review)
Review
Potassium channels, tetrameric integral membrane proteins that form aqueous pores through which K+ can flow, are found in virtually all organisms; the genomes of humans, Drosophila, and Caenorhabditis elegans contain 30-100 K+ channel genes each. The structure of a bacterial K+ channel, sequence comparisons with other channels and electrophysiological measurements have enabled conclusions about the mechanism of gating and ion flow to be drawn for many other channels.
Topics: Animals; Evolution, Molecular; Humans; Ion Channel Gating; Models, Molecular; Potassium Channels; Protein Conformation
PubMed: 11178249
DOI: 10.1186/gb-2000-1-4-reviews0004