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Proceedings of the National Academy of... Oct 2018A primary goal of sleep research is to understand the molecular basis of sleep. Although some sleep/wake-promoting circuits and secreted substances have been identified,...
A primary goal of sleep research is to understand the molecular basis of sleep. Although some sleep/wake-promoting circuits and secreted substances have been identified, the detailed molecular mechanisms underlying the regulation of sleep duration have been elusive. Here, to address these mechanisms, we developed a simple computational model of a cortical neuron with five channels and a pump, which recapitulates the cortical electrophysiological characteristics of slow-wave sleep (SWS) and wakefulness. Comprehensive bifurcation and detailed mathematical analyses predicted that leak K channels play a role in generating the electrophysiological characteristics of SWS, leading to a hypothesis that leak K channels play a role in the regulation of sleep duration. To test this hypothesis experimentally, we comprehensively generated and analyzed 14 KO mice, and found that impairment of the leak K channel () decreased sleep duration. Based on these results, we hypothesize that leak K channels regulate sleep duration in mammals.
Topics: Animals; Brain Waves; Mice; Mice, Knockout; Potassium Channels; Sleep Stages
PubMed: 30224462
DOI: 10.1073/pnas.1806486115 -
Expert Opinion on Therapeutic Targets 2024Kv1.3 is the main voltage-gated potassium channel of leukocytes from both the innate and adaptive immune systems. Channel function is required for common processes such... (Review)
Review
INTRODUCTION
Kv1.3 is the main voltage-gated potassium channel of leukocytes from both the innate and adaptive immune systems. Channel function is required for common processes such as Ca signaling but also for cell-specific events. In this context, alterations in Kv1.3 are associated with multiple immune disorders. Excessive channel activity correlates with numerous autoimmune diseases, while reduced currents result in increased cancer prevalence and immunodeficiencies.
AREAS COVERED
This review offers a general view of the role of Kv1.3 in every type of leukocyte. Moreover, diseases stemming from dysregulations of the channel are detailed, as well as current advances in their therapeutic research.
EXPERT OPINION
Kv1.3 arises as a potential immune target in a variety of diseases. Several lines of research focused on channel modulation have yielded positive results. However, among the great variety of specific channel blockers, only one has reached clinical trials. Future investigations should focus on developing simpler administration routes for channel inhibitors to facilitate their entrance into clinical trials. Prospective Kv1.3-based treatments will ensure powerful therapies while minimizing undesired side effects.
Topics: Humans; Prospective Studies; Potassium Channels, Voltage-Gated; Autoimmune Diseases; Signal Transduction; Kv1.3 Potassium Channel; Potassium Channel Blockers
PubMed: 38316438
DOI: 10.1080/14728222.2024.2315021 -
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 -
The Journal of General Physiology Mar 2023Charge-voltage curves of many voltage-gated ion channels exhibit hysteresis but such curves are also a direct measure of free energy of channel gating and, hence, should...
Charge-voltage curves of many voltage-gated ion channels exhibit hysteresis but such curves are also a direct measure of free energy of channel gating and, hence, should be path-independent. Here, we identify conditions to measure steady-state charge-voltage curves and show that these are curves are not hysteretic. Charged residues in transmembrane segments of voltage-gated ion channels (VGICs) sense and respond to changes in the electric field. The movement of these gating charges underpins voltage-dependent activation and is also a direct metric of the net free-energy of channel activation. However, for most voltage-gated ion channels, the charge-voltage (Q-V) curves appear to be dependent on initial conditions. For instance, Q-V curves of Shaker potassium channel obtained by hyperpolarizing from 0 mV is left-shifted compared to those obtained by depolarizing from a holding potential of -80 mV. This hysteresis in Q-V curves is a common feature of channels in the VGIC superfamily and raises profound questions about channel energetics because the net free-energy of channel gating is a state function and should be path independent. Due to technical limitations, conventional gating current protocols are limited to test pulse durations of <500 ms, which raises the possibility that the dependence of Q-V on initial conditions reflects a lack of equilibration. Others have suggested that the hysteresis is fundamental thermodynamic property of voltage-gated ion channels and reflects energy dissipation due to measurements under non-equilibrium conditions inherent to rapid voltage jumps (Villalba-Galea. 2017. Channels. https://doi.org/10.1080/19336950.2016.1243190). Using an improved gating current and voltage-clamp fluorometry protocols, we show that the gating hysteresis arising from different initial conditions in Shaker potassium channel is eliminated with ultra-long (18-25 s) test pulses. Our study identifies a modified gating current recording protocol to obtain steady-state Q-V curves of a voltage-gated ion channel. Above all, these findings demonstrate that the gating hysteresis in Shaker channel is a kinetic phenomenon rather than a true thermodynamic property of the channel and the charge-voltage curve is a true measure of the net-free energy of channel gating.
Topics: Potassium Channels; Membrane Potentials; Ion Channel Gating; Shaker Superfamily of Potassium Channels; Oocytes
PubMed: 36692860
DOI: 10.1085/jgp.202112883 -
Neuroscience Bulletin Oct 2018General anesthesia is an unconscious state induced by anesthetics for surgery. The molecular targets and cellular mechanisms of general anesthetics in the mammalian... (Review)
Review
General anesthesia is an unconscious state induced by anesthetics for surgery. The molecular targets and cellular mechanisms of general anesthetics in the mammalian nervous system have been investigated during past decades. In recent years, K channels have been identified as important targets of both volatile and intravenous anesthetics. This review covers achievements that have been made both on the regulatory effect of general anesthetics on the activity of K channels and their underlying mechanisms. Advances in research on the modulation of K channels by general anesthetics are summarized and categorized according to four large K channel families based on their amino-acid sequence homology. In addition, research achievements on the roles of K channels in general anesthesia in vivo, especially with regard to studies using mice with K channel knockout, are particularly emphasized.
Topics: Anesthetics, General; Animals; Humans; Potassium Channels
PubMed: 29948841
DOI: 10.1007/s12264-018-0239-1 -
The Journal of Neuroscience : the... Sep 2023Gain-of-function (GOF) pathogenic variants in the potassium channels KCNQ2 and KCNQ3 lead to hyperexcitability disorders such as epilepsy and autism spectrum disorders....
Gain-of-function (GOF) pathogenic variants in the potassium channels KCNQ2 and KCNQ3 lead to hyperexcitability disorders such as epilepsy and autism spectrum disorders. However, the underlying cellular mechanisms of how these variants impair forebrain function are unclear. Here, we show that the R201C variant in KCNQ2 has opposite effects on the excitability of two types of mouse pyramidal neurons of either sex, causing hyperexcitability in layer 2/3 (L2/3) pyramidal neurons and hypoexcitability in CA1 pyramidal neurons. Similarly, the homologous R231C variant in KCNQ3 leads to hyperexcitability in L2/3 pyramidal neurons and hypoexcitability in CA1 pyramidal neurons. However, the effects of KCNQ3 gain-of-function on excitability are specific to superficial CA1 pyramidal neurons. These findings reveal a new level of complexity in the function of KCNQ2 and KCNQ3 channels in the forebrain and provide a framework for understanding the effects of gain-of-function variants and potassium channels in the brain. KCNQ2/3 gain-of-function (GOF) variants lead to severe forms of neurodevelopmental disorders, but the mechanisms by which these channels affect neuronal activity are poorly understood. In this study, using a series of transgenic mice we demonstrate that the same KCNQ2/3 GOF variants can lead to either hyperexcitability or hypoexcitability in different types of pyramidal neurons [CA1 vs layer (L)2/3]. Additionally, we show that expression of the recurrent KCNQ2 GOF variant R201C in forebrain pyramidal neurons could lead to seizures and SUDEP. Our data suggest that the effects of KCNQ2/3 GOF variants depend on specific cell types and brain regions, possibly accounting for the diverse range of phenotypes observed in individuals with KCNQ2/3 GOF variants.
Topics: Animals; Mice; Gain of Function Mutation; KCNQ2 Potassium Channel; Mice, Transgenic; Neurodevelopmental Disorders; Potassium Channels; Prosencephalon; Pyramidal Cells; KCNQ3 Potassium Channel
PubMed: 37607817
DOI: 10.1523/JNEUROSCI.0980-23.2023 -
Advances in Experimental Medicine and... 2021The KCNT1 gene encodes the sodium-activated potassium channel that is abundantly expressed in the central nervous system of mammalians and plays an important role in... (Review)
Review
The KCNT1 gene encodes the sodium-activated potassium channel that is abundantly expressed in the central nervous system of mammalians and plays an important role in reducing neuronal excitability. Structurally, the KCNT1 channel is absent of voltage sensor but possesses a long C-terminus including RCK1 and RCK2domain, to which the intracellular sodium and chloride bind to activate the channel. Recent publications using electron cryo-microscopy (cryo-EM) revealed the open and closed structural characteristics of the KCNT1 channel and co-assembly of functional domains. The activation of the KCNT1 channel regulates various physiological processes including nociceptive behavior, itch, spatial learning. Meanwhile, malfunction of this channel causes important pathophysiological consequences, including Fragile X syndrome and a wide spectrum of seizure disorders. This review comprehensively describes the structure, expression patterns, physiological functions of the KCNT1 channel and emphasizes the channelopathy of gain-of-function KCNT1 mutations in epilepsy.
Topics: Animals; Channelopathies; Epilepsy; Mutation; Nerve Tissue Proteins; Potassium Channels; Potassium Channels, Sodium-Activated
PubMed: 35138624
DOI: 10.1007/978-981-16-4254-8_18 -
Histology and Histopathology Jan 2023There are two kinds of toxins in sea anemones: neurotoxins and pore forming toxins. As a representative of the sodium channel toxin, the neurotoxin ATX II in neurotoxin... (Review)
Review
There are two kinds of toxins in sea anemones: neurotoxins and pore forming toxins. As a representative of the sodium channel toxin, the neurotoxin ATX II in neurotoxin mainly affects the process of action potential and the release of transmitter to affect the inactivation of the sodium channel. As the representatives of potassium channel toxins, BgK and ShK mainly affect the potassium channel current. EqTx and Sticholysins are representative of pore forming toxins, which can form specific ion channels in cell membranes and change the concentration of internal and external ions, eventually causing hemolytic effects. Based on the above mechanism, toxins such as ATX II can also cause toxic effects in tissues and organs such as heart, lung and muscle. As an applied aspect it was shown that sea anemone toxins often have strong toxic effects on tumor cells, induce cancer cells to enter the pathway of apoptosis, and can also bind to monoclonal antibodies or directly inhibit relevant channels for the treatment of autoimmune diseases.
Topics: Animals; Neurotoxins; Sea Anemones; Sodium Channels; Potassium Channels; Cell Membrane
PubMed: 35880756
DOI: 10.14670/HH-18-500 -
Biomolecules Sep 2020Pulmonary arterial hypertension (PAH) is a rare and severe cardiopulmonary disease without curative treatments. PAH is a multifactorial disease that involves genetic... (Review)
Review
Pulmonary arterial hypertension (PAH) is a rare and severe cardiopulmonary disease without curative treatments. PAH is a multifactorial disease that involves genetic predisposition, epigenetic factors, and environmental factors (drugs, toxins, viruses, hypoxia, and inflammation), which contribute to the initiation or development of irreversible remodeling of the pulmonary vessels. The recent identification of loss-of-function mutations in (KCNK3 or TASK-1) and (SUR1), or gain-of-function mutations in (SUR2), as well as polymorphisms in (Kv1.5), which encode two potassium (K) channels and two K channel regulatory subunits, has revived the interest of ion channels in PAH. This review focuses on KCNK3, SUR1, SUR2, and Kv1.5 channels in pulmonary vasculature and discusses their pathophysiological contribution to and therapeutic potential in PAH.
Topics: Animals; Drug Delivery Systems; Humans; Kv1.5 Potassium Channel; Nerve Tissue Proteins; Potassium Channels; Potassium Channels, Inwardly Rectifying; Potassium Channels, Tandem Pore Domain; Pulmonary Arterial Hypertension; Sulfonylurea Receptors
PubMed: 32882918
DOI: 10.3390/biom10091261 -
Expert Opinion on Drug Discovery Feb 2015Cardiac K(+) channels play a critical role in maintaining the normal electrical activity of the heart by setting the cell resting membrane potential and by determining... (Review)
Review
INTRODUCTION
Cardiac K(+) channels play a critical role in maintaining the normal electrical activity of the heart by setting the cell resting membrane potential and by determining the shape and duration of the action potential. Drugs that block the rapid (IKr) and slow (IKs) components of the delayed rectifier K(+) current have been widely used as class III antiarrhythmic agents. In addition, drugs that selectively target the ultra-rapid delayed rectifier current (IKur) and the acetylcholine-gated inward rectifier current (IKAch) have shown efficacy in the treatment of patients with atrial fibrillation. In order to meet the future demand for new antiarrhythmic agents, novel approaches for cardiac K(+) channel drug discovery will need to be developed. Further, K(+) channel screening assays utilizing primary and stem cell-derived cardiomyocytes will be essential for evaluating the cardiotoxicity of potential drug candidates.
AREAS COVERED
In this review, the author provides a brief background on the structure, function and pharmacology of cardiac voltage-gated and inward rectifier K(+) channels. He then focuses on describing and evaluating current technologies, such as ion flux and membrane potential-sensitive dye assays, used for cardiac K(+) channel drug discovery.
EXPERT OPINION
Cardiac K(+) channels will continue to represent significant clinical targets for drug discovery. Although fluorescent high-throughput screening (HTS) assays and automated patch clamp systems will remain the workhorse technologies for identifying lead compounds, innovations in the areas of microfluidics, micropatterning and biosensor fabrication will allow further growth of technologies using primary and stem cell-derived cardiomyocytes.
Topics: Animals; Anti-Arrhythmia Agents; Drug Discovery; Humans; Ion Channel Gating; Membrane Potentials; Molecular Targeted Therapy; Myocardium; Myocytes, Cardiac; Patch-Clamp Techniques; Potassium Channel Blockers; Potassium Channels
PubMed: 25400064
DOI: 10.1517/17460441.2015.983471