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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 -
ELife Jun 2023Voltage-gated potassium (K) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. K channel...
Voltage-gated potassium (K) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. K channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability, a characteristic of epilepsy and cardiac arrhythmias. Interventions intended to restore K channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of K channel activators with potential applications in the treatment of arrhythmogenic disorders such as long QT syndrome (LQTS). LQTS is caused by a loss-of-function of the cardiac I channel - a tetrameric potassium channel complex formed by K7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac I channel, and a unique feature of these PUFA analogues is an aromatic, tyrosine head group. We determine the mechanisms through which tyrosine PUFA analogues exert strong activating effects on the I channel by generating modified aromatic head groups designed to probe cation-pi interactions, hydrogen bonding, and ionic interactions. We found that tyrosine PUFA analogues do not activate the I channel through cation-pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.
Topics: Humans; Potassium Channels; Potassium Channels, Voltage-Gated; KCNQ1 Potassium Channel; Fatty Acids, Unsaturated; Long QT Syndrome; Arrhythmias, Cardiac; Tyrosine
PubMed: 37350568
DOI: 10.7554/eLife.85773 -
Current Topics in Medicinal Chemistry 2017The rapid delayed rectifier current IKr is one of the major K+ currents involved in repolarization of the human cardiac action potential. Various inherited or... (Review)
Review
The rapid delayed rectifier current IKr is one of the major K+ currents involved in repolarization of the human cardiac action potential. Various inherited or drug-induced forms of the long QT syndrome (LQTS) in humans are linked to functional and structural modifications in the IKr conducting channels. IKr is carried by the potassium channel Kv11.1 encoded by the gene KCNH2 (commonly referred to as human ether-a-go-go-related gene or hERG) [1, 2]. The first necessary step for predicting emergent drug effects on the heart is determining and modeling the binding thermodynamics and kinetics of primary and major off-target drug interactions with subcellular targets. The bulk of drugs that target hERG channels are known to have complex interactions at the atomic scale. Accordingly, one of the goals for this review is to provide comprehensive guide in the universe of computational models aiming to refine our understanding of structure-function relations in Kv11.1 and its isoforms. The special emphasis is placed on the mapping of drug binding sites and tentative mechanisms of channel inhibition and activation by drugs. An overview over recent structural models and mapping of binding sites for blockers and activators of IKr current along with the discussion on agreements and discrepancies among different models is presented. There is an apparent reciprocity or feedback loop between drug binding and action potential of the cardiac myocytes. Thus one has to connect drug binding to a particular receptor so that its functional consequences impact on the action potential duration. The natural pathway is to develop multi-scale models that connect between receptor and cellular scales. The potential for such multi-scale model development is discussed through the lens of common gating models. Accordingly, the second part of this review covers an ongoing development of the kinetic models of gating transitions and cardiac ion currents carried by hERG channels with and without drug bound.
Topics: Ether-A-Go-Go Potassium Channels; Heart; Humans; Models, Molecular
PubMed: 28413954
DOI: 10.2174/1568026617666170414143430 -
Gene Sep 2015The KCNE single-span transmembrane subunits are encoded by five-member gene families in the human and mouse genomes. Primarily recognized for co-assembling with and... (Review)
Review
The KCNE single-span transmembrane subunits are encoded by five-member gene families in the human and mouse genomes. Primarily recognized for co-assembling with and functionally regulating the voltage-gated potassium channels, the broad influence of KCNE subunits in mammalian physiology belies their small size. KCNE2 has been widely studied since we first discovered one of its roles in the heart and its association with inherited and acquired human Long QT syndrome. Since then, physiological analyses together with human and mouse genetics studies have uncovered a startling array of functions for KCNE2, in the heart, stomach, thyroid and choroid plexus. The other side of this coin is the variety of interconnected disease manifestations caused by KCNE2 disruption, involving both excitable cells such as cardiomyocytes, and non-excitable, polarized epithelia. Kcne2 deletion in mice has been particularly instrumental in illustrating the potential ramifications within a monogenic arrhythmia syndrome, with removal of one piece revealing the unexpected complexity of the puzzle. Here, we review current knowledge of the function and pathobiology of KCNE2.
Topics: Animals; Arrhythmias, Cardiac; Electrophysiology; Heart; Humans; Potassium Channels, Voltage-Gated
PubMed: 26123744
DOI: 10.1016/j.gene.2015.06.061 -
Biochimica Et Biophysica Acta Oct 2015Potassium channels are a diverse group of pore-forming transmembrane proteins that selectively facilitate potassium flow through an electrochemical gradient. They... (Review)
Review
Potassium channels are a diverse group of pore-forming transmembrane proteins that selectively facilitate potassium flow through an electrochemical gradient. They participate in the control of the membrane potential and cell excitability in addition to different cell functions such as cell volume regulation, proliferation, cell migration, angiogenesis as well as apoptosis. Because these physiological processes are essential for the correct cell function, K+ channels have been associated with a growing number of diseases including cancer. In fact, different K+ channel families such as the voltage-gated K+ channels, the ether à-go-go K+ channels, the two pore domain K+ channels and the Ca2+-activated K+ channels have been associated to tumor biology. Potassium channels have a role in neoplastic cell-cycle progression and their expression has been found abnormal in many types of tumors and cancer cells. In addition, the expression and activity of specific K+ channels have shown a significant correlation with the tumor malignancy grade. The aim of this overview is to summarize published data on K+ channels that exhibit oncogenic properties and have been linked to a more malignant cancer phenotype. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers.
Topics: Apoptosis; Cell Movement; Cell Proliferation; Cell Size; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Membrane Potentials; Neoplasms; Neovascularization, Pathologic; Phenotype; Potassium; Potassium Channel Blockers; Potassium Channels, Calcium-Activated; Potassium Channels, Tandem Pore Domain; Potassium Channels, Voltage-Gated
PubMed: 25517985
DOI: 10.1016/j.bbamem.2014.12.008 -
The Journal of Physiology Jun 2015The gating of the KCNQ1 potassium channel is drastically regulated by auxiliary subunit KCNE proteins. KCNE1, for example, slows the activation kinetics of KCNQ1 by two... (Review)
Review
The gating of the KCNQ1 potassium channel is drastically regulated by auxiliary subunit KCNE proteins. KCNE1, for example, slows the activation kinetics of KCNQ1 by two orders of magnitude. Like other voltage-gated ion channels, the opening of KCNQ1 is regulated by the voltage-sensing domain (VSD; S1-S4 segments). Although it has been known that KCNE proteins interact with KCNQ1 via the pore domain, some recent reports suggest that the VSD movement may be altered by KCNE. The altered VSD movement of KCNQ1 by KCNE proteins has been examined by site-directed mutagenesis, the scanning cysteine accessibility method (SCAM), voltage clamp fluorometry (VCF) and gating charge measurements. These accumulated data support the idea that KCNE proteins interact with the VSDs of KCNQ1 and modulate the gating of the KCNQ1 channel. In this review, we will summarize recent findings and current views of the KCNQ1 modulation by KCNE via the VSD. In this context, we discuss our recent findings that KCNE1 may alter physical interactions between the S4 segment (VSD) and the S5 segment (pore domain) of KCNQ1. Based on these findings from ourselves and others, we propose a hypothetical mechanism for how KCNE1 binding alters the VSD movement and the gating of the channel.
Topics: Animals; Potassium Channels, Voltage-Gated; Protein Structure, Tertiary
PubMed: 25603957
DOI: 10.1113/jphysiol.2014.287672 -
Orphanet Journal of Rare Diseases Sep 2022Novel developmental mutations associated with disease are a continuous challenge in medicine. Clinical consequences caused by these mutations include neuron and...
BACKGROUND
Novel developmental mutations associated with disease are a continuous challenge in medicine. Clinical consequences caused by these mutations include neuron and cognitive alterations that can lead to epilepsy or autism spectrum disorders. Often, it is difficult to identify the physiological defects and the appropriate treatments.
RESULTS
We have isolated and cultured primary cells from the skin of a patient with combined epilepsy and autism syndrome. A mutation in the potassium channel protein Kv10.2 was identified. We have characterised the alteration of the mutant channel and found that it causes loss of function (LOF). Primary cells from the skin displayed a very striking growth defect and increased differentiation. In vitro treatment with various carbonic anhydrase inhibitors with various degrees of specificity for potassium channels, (Brinzolamide, Acetazolamide, Retigabine) restored the activation capacity of the mutated channel. Interestingly, the drugs also recovered in vitro the expansion capacity of the mutated skin cells. Furthermore, treatment with Acetazolamide clearly improved the patient regarding epilepsy and cognitive skills. When the treatment was temporarily halted the syndrome worsened again.
CONCLUSIONS
By in vitro studying primary cells from the patient and the activation capacity of the mutated protein, we could first, find a readout for the cellular defects and second, test pharmaceutical treatments that proved to be beneficial. The results show the involvement of a novel LOF mutation of a Potassium channel in autism syndrome with epilepsy and the great potential of in vitro cultures of primary cells in personalised medicine of rare diseases.
Topics: Acetazolamide; Autistic Disorder; Epilepsy; Humans; Mutation; Potassium Channels; Potassium Channels, Voltage-Gated
PubMed: 36068614
DOI: 10.1186/s13023-022-02499-z -
Channels (Austin, Tex.) Dec 2024K channels are ligand-gated potassium channels that couple cellular energetics with membrane potential to regulate cell activity. Each channel is an eight subunit... (Review)
Review
K channels are ligand-gated potassium channels that couple cellular energetics with membrane potential to regulate cell activity. Each channel is an eight subunit complex comprising four central pore-forming Kir6 inward rectifier potassium channel subunits surrounded by four regulatory subunits known as the sulfonylurea receptor, SUR, which confer homeostatic metabolic control of K gating. SUR is an ATP binding cassette (ABC) protein family homolog that lacks membrane transport activity but is essential for K expression and function. For more than four decades, understanding the structure-function relationship of Kir6 and SUR has remained a central objective of clinical significance. Here, we review progress in correlating the wealth of functional data in the literature with recent K cryoEM structures.
Topics: Sulfonylurea Receptors; Potassium Channels, Inwardly Rectifying; Membrane Potentials; Adenosine Triphosphate; KATP Channels
PubMed: 38489043
DOI: 10.1080/19336950.2024.2327708 -
Cardiac Electrophysiology Clinics Jun 2016Approximately 80 genes in the human genome code for pore-forming subunits of potassium (K(+)) channels. Rare variants (mutations) in K(+) channel-encoding genes may... (Review)
Review
Approximately 80 genes in the human genome code for pore-forming subunits of potassium (K(+)) channels. Rare variants (mutations) in K(+) channel-encoding genes may cause heritable arrhythmia syndromes. Not all rare variants in K(+) channel-encoding genes are necessarily disease-causing mutations. Common variants in K(+) channel-encoding genes are increasingly recognized as modifiers of phenotype in heritable arrhythmia syndromes and in the general population. Although difficult, distinguishing pathogenic variants from benign variants is of utmost importance to avoid false designations of genetic variants as disease-causing mutations.
Topics: Arrhythmias, Cardiac; Humans; Mutation; Phenotype; Potassium Channels
PubMed: 27261822
DOI: 10.1016/j.ccep.2016.01.003 -
Pediatric Cardiology Jan 2017Many different types of potassium channels with various functions exist in pulmonary artery smooth muscle cells, contributing to many physiological actions and... (Review)
Review
Many different types of potassium channels with various functions exist in pulmonary artery smooth muscle cells, contributing to many physiological actions and pathological conditions. The deep involvement of these channels in the onset and exacerbation of pulmonary arterial hypertension (PAH) also continues to be revealed. In 2013, KCNK3 (TASK1), which encodes a type of two-pore domain potassium channel, was shown to be a predisposing gene for PAH by genetic mutation, and it was added to the PAH classification at the Fifth World Symposium on Pulmonary Hypertension (Nice International Conference). Decreased expression and inhibited activity of voltage-gated potassium channels, particularly KCNA5 (Kv1.5), are also seen in PAH, regardless of the cause, and facilitation of pulmonary arterial contraction and vascular remodeling has been shown. The calcium-activated potassium channels seen in smooth muscle cells also change from BKca (Kca1.1) to IKca (Kca3.1) predominance in PAH due to transformation and have effects including the facilitation of smooth muscle cell migration, enhancement of proliferation, and inhibition of apoptosis. Elucidation of these roles for potassium channels in pulmonary vasoconstriction and remodeling may help bring new therapeutic strategies into view.
Topics: Animals; Humans; Hypertension, Pulmonary; Membrane Potentials; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Potassium Channels; Pulmonary Artery; Vascular Remodeling; Vasoconstriction
PubMed: 27826710
DOI: 10.1007/s00246-016-1491-7