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Genes & Diseases Jul 2024Diabetic kidney disease is a leading cause of end-stage renal disease, making it a global public health concern. The molecular mechanisms underlying diabetic kidney... (Review)
Review
Diabetic kidney disease is a leading cause of end-stage renal disease, making it a global public health concern. The molecular mechanisms underlying diabetic kidney disease have not been elucidated due to its complex pathogenesis. Thus, exploring these mechanisms from new perspectives is the current focus of research concerning diabetic kidney disease. Ion channels are important proteins that maintain the physiological functions of cells and organs. Among ion channels, potassium channels stand out, because they are the most common and important channels on eukaryotic cell surfaces and function as the basis for cell excitability. Certain potassium channel abnormalities have been found to be closely related to diabetic kidney disease progression and genetic susceptibility, such as K, K, K, and K. In this review, we summarized the roles of different types of potassium channels in the occurrence and development of diabetic kidney disease to discuss whether the development of DKD is due to potassium channel dysfunction and present new ideas for the treatment of DKD.
PubMed: 38523672
DOI: 10.1016/j.gendis.2023.101119 -
Pharmaceuticals (Basel, Switzerland) Aug 2023()-encoded potassium channels underlie the cardiac rapid delayed rectifier (I) potassium current, which is a major target for antiarrhythmic agents and diverse...
()-encoded potassium channels underlie the cardiac rapid delayed rectifier (I) potassium current, which is a major target for antiarrhythmic agents and diverse non-cardiac drugs linked to the drug-induced form of long QT syndrome. E-4031 is a high potency hERG channel inhibitor from the methanesulphonanilide drug family. This study utilized a methanesulphonate-lacking E-4031 analogue, "E-4031-17", to evaluate the role of the methanesulphonamide group in E-4031 inhibition of hERG. Whole-cell patch-clamp measurements of the hERG current (I) were made at physiological temperature from HEK 293 cells expressing wild-type (WT) and mutant hERG constructs. For E-4031, WT I was inhibited by a half-maximal inhibitory concentration (IC) of 15.8 nM, whilst the comparable value for E-4031-17 was 40.3 nM. Both compounds exhibited voltage- and time-dependent inhibition, but they differed in their response to successive applications of a long (10 s) depolarisation protocol, consistent with greater dissociation of E-4031-17 than the parent compound between applied commands. Voltage-dependent inactivation was left-ward voltage shifted for E-4031 but not for E-4031-17; however, inhibition by both compounds was strongly reduced by attenuated-inactivation mutations. Mutations of S6 and S5 aromatic residues (F656V, Y652A, F557L) greatly attenuated actions of both drugs. The S624A mutation also reduced I inhibition by both molecules. Overall, these results demonstrate that the lack of a methanesulphonate in E-4031-17 is not an impediment to high potency inhibition of I.
PubMed: 37765012
DOI: 10.3390/ph16091204 -
Biomedicine & Pharmacotherapy =... Feb 2024Small conductance calcium-activated potassium (SK) channel activity has been proposed to play a role in the pathology of several neurological diseases. Besides...
Small conductance calcium-activated potassium (SK) channel activity has been proposed to play a role in the pathology of several neurological diseases. Besides regulating plasma membrane excitability, SK channel activation provides neuroprotection against ferroptotic cell death by reducing mitochondrial Ca uptake and reactive oxygen species (ROS). In this study, we employed a multifaceted approach, integrating structure-based and computational techniques, to strategically design and synthesize an innovative class of potent small-molecule SK2 channel modifiers through highly efficient multicomponent reactions (MCRs). The compounds' neuroprotective activity was compared with the well-studied SK positive modulator, CyPPA. Pharmacological SK channel activation by selected compounds confers neuroprotection against ferroptosis at low nanomolar ranges compared to CyPPA, that mediates protection at micromolar concentrations, as shown by an MTT assay, real-time cell impedance measurements and propidium iodide staining (PI). These novel compounds suppress increased mitochondrial ROS and Ca level induced by ferroptosis inducer RSL3. Moreover, axonal degeneration was rescued by these novel SK channel activators in primary mouse neurons and they attenuated glutamate-induced neuronal excitability, as shown via microelectrode array. Meanwhile, functional afterhyperpolarization of the novel SK2 channel modulators was validated by electrophysiological measurements showing more current change induced by the novel modulators than the reference compound, CyPPA. These data support the notion that SK2 channel activation can represent a therapeutic target for brain diseases in which ferroptosis and excitotoxicity contribute to the pathology.
Topics: Mice; Animals; Small-Conductance Calcium-Activated Potassium Channels; Reactive Oxygen Species; Ferroptosis; Neurons; Mitochondria
PubMed: 38242037
DOI: 10.1016/j.biopha.2024.116163 -
Proceedings of the National Academy of... Dec 2023In a family with inappropriate sinus tachycardia (IST), we identified a mutation (p.V240M) of the hyperpolarization-activated cyclic nucleotide-gated type 4 (HCN4)...
In a family with inappropriate sinus tachycardia (IST), we identified a mutation (p.V240M) of the hyperpolarization-activated cyclic nucleotide-gated type 4 (HCN4) channel, which contributes to the pacemaker current (I) in human sinoatrial node cells. Here, we clinically study fifteen family members and functionally analyze the p.V240M variant. Macroscopic (I) and single-channel currents were recorded using patch-clamp in cells expressing human native (WT) and/or p.V240M HCN4 channels. All p.V240M mutation carriers exhibited IST that was accompanied by cardiomyopathy in adults. I generated by p.V240M channels either alone or in combination with WT was significantly greater than that generated by WT channels alone. The variant, which lies in the N-terminal HCN domain, increased the single-channel conductance and opening frequency and probability of HCN4 channels. Conversely, it did not modify the channel sensitivity for cAMP and ivabradine or the level of expression at the membrane. Treatment with ivabradine based on functional data reversed the IST and the cardiomyopathy of the carriers. In computer simulations, the p.V240M gain-of-function variant increases I and beating rate and thus explains the IST of the carriers. The results demonstrate the importance of the unique HCN domain in HCN4, which stabilizes the channels in the closed state.
Topics: Adult; Humans; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Tachycardia, Sinus; Potassium Channels; Ivabradine; Cyclic Nucleotide-Gated Cation Channels; Gain of Function Mutation; Muscle Proteins; Sinoatrial Node; Cardiomyopathies
PubMed: 38032931
DOI: 10.1073/pnas.2305135120 -
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 -
Acta Biochimica Polonica 2024Mitochondrial investigations have extended beyond their traditional functions, covering areas such as ATP synthesis and metabolism. Mitochondria are now implicated in... (Review)
Review
Mitochondrial investigations have extended beyond their traditional functions, covering areas such as ATP synthesis and metabolism. Mitochondria are now implicated in new functional areas such as cytoprotection, cellular senescence, tumor function and inflammation. The basis of these new areas still relies on fundamental biochemical/biophysical mitochondrial functions such as synthesis of reactive oxygen species, mitochondrial membrane potential, and the integrity of the inner mitochondrial membrane i.e., the passage of various molecules through the mitochondrial membranes. In this view transport of potassium cations, known as the potassium cycle, plays an important role. It is believed that K influx is mediated by various potassium channels present in the inner mitochondrial membrane. In this article, we present an overview of the key findings and characteristics of mitochondrial potassium channels derived from research of many groups conducted over the past 33 years. We propose a list of six fundamental observations and most important ideas dealing with mitochondrial potassium channels. We also discuss the contemporary challenges and future prospects associated with research on mitochondrial potassium channels.
Topics: Humans; Mitochondria; Potassium Channels; Animals; Potassium; Mitochondrial Membranes; Membrane Potential, Mitochondrial; Reactive Oxygen Species
PubMed: 38863652
DOI: 10.3389/abp.2024.13126 -
Mitochondrion May 2024Ageing is described as an inevitable decline in body functions over time and an increase in susceptibility to age-related diseases. Therefore, the increase of life... (Review)
Review
Ageing is described as an inevitable decline in body functions over time and an increase in susceptibility to age-related diseases. Therefore, the increase of life expectancy is also viewed as a condition in which many elderly will develop age-related diseases and disabilities, such as cardiovascular, metabolic, neurological and oncological ones. Currently, several recognized cellular hallmarks of senescence are taken in consideration to evaluate the level of biological ageing and are the topic to plan preventive/curative anti-ageing interventions, including genomic instability, epigenetic alterations, and mitochondrial dysfunction. In this scenario, alterations in the function/expression of mitochondrial ion channels have been found in ageing and associated to an impairment of calcium cycling and a reduced mitochondrial membrane potential. Although several ion channels have been described at mitochondrial level, undoubtedly the mitochondrial potassium (mitoK) channels are the most investigated. Therefore, this review summarized the evidence that sheds to light a correlation between age-related diseases and alteration of mitoK channels, focusing the attention of the main age-related diseases, i.e. cardiovascular, neurological and oncological ones.
Topics: Humans; Aging; Potassium Channels; Mitochondria; Animals
PubMed: 38403095
DOI: 10.1016/j.mito.2024.101857 -
International Journal of Molecular... Apr 2024Alterations in intraocular and external pressure critically involve the pathogenesis of glaucoma, traumatic retinal injury (TRI), and other retinal disorders, and... (Review)
Review
Alterations in intraocular and external pressure critically involve the pathogenesis of glaucoma, traumatic retinal injury (TRI), and other retinal disorders, and retinal neurons have been reported to express multiple mechanical-sensitive channels (MSCs) in recent decades. However, the role of MSCs in visual functions and pressure-related retinal conditions has been unclear. This review will focus on the variety and functional significance of the MSCs permeable to K, Na, and Ca, primarily including the big potassium channel (BK); the two-pore domain potassium channels TRAAK and TREK; Piezo; the epithelial sodium channel (ENaC); and the transient receptor potential channels vanilloid TRPV1, TRPV2, and TRPV4 in retinal photoreceptors, bipolar cells, horizontal cells, amacrine cells, and ganglion cells. Most MSCs do not directly mediate visual signals in vertebrate retinas. On the other hand, some studies have shown that MSCs can open in physiological conditions and regulate the activities of retinal neurons. While these data reasonably predict the crossing of visual and mechanical signals, how retinal light pathways deal with endogenous and exogenous mechanical stimulation is uncertain.
Topics: Humans; Animals; Ion Channels; Retinal Neurons; Mechanotransduction, Cellular; Retina
PubMed: 38732096
DOI: 10.3390/ijms25094877 -
PLoS Biology Aug 2023It is well known that the neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons increase appetite and decrease thermogenesis. Previous studies demonstrated that...
It is well known that the neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons increase appetite and decrease thermogenesis. Previous studies demonstrated that optogenetic and/or chemogenetic manipulations of NPY/AgRP neuronal activity alter food intake and/or energy expenditure (EE). However, little is known about intrinsic molecules regulating NPY/AgRP neuronal excitability to affect long-term metabolic function. Here, we found that the G protein-gated inwardly rectifying K+ (GIRK) channels are key to stabilize NPY/AgRP neurons and that NPY/AgRP neuron-selective deletion of the GIRK2 subunit results in a persistently increased excitability of the NPY/AgRP neurons. Interestingly, increased body weight and adiposity observed in the NPY/AgRP neuron-selective GIRK2 knockout mice were due to decreased sympathetic activity and EE, while food intake remained unchanged. The conditional knockout mice also showed compromised adaptation to coldness. In summary, our study identified GIRK2 as a key determinant of NPY/AgRP neuronal excitability and driver of EE in physiological and stress conditions.
Topics: Animals; Mice; Adiposity; Agouti-Related Protein; Body Weight; Mice, Knockout; Neurons; Obesity; Peptides; G Protein-Coupled Inwardly-Rectifying Potassium Channels
PubMed: 37594983
DOI: 10.1371/journal.pbio.3002252 -
International Journal of Molecular... Aug 2023Glioblastoma (GBM) is the most malignant form of primary brain tumor. It is characterized by the presence of highly invasive cancer cells infiltrating the brain by...
Glioblastoma (GBM) is the most malignant form of primary brain tumor. It is characterized by the presence of highly invasive cancer cells infiltrating the brain by hijacking neuronal mechanisms and interacting with non-neuronal cell types, such as astrocytes and endothelial cells. To enter the interstitial space of the brain parenchyma, GBM cells significantly shrink their volume and extend the invadopodia and lamellipodia by modulating their membrane conductance repertoire. However, the changes in the compartment-specific ionic dynamics involved in this process are still not fully understood. Here, using noninvasive perforated patch-clamp and live imaging approaches on various GBM cell lines during a wound-healing assay, we demonstrate that the sodium-calcium exchanger (NCX) is highly expressed in the lamellipodia compartment, is functionally active during GBM cell migration, and correlates with the overexpression of large conductance K+ channel (BK) potassium channels. Furthermore, a NCX blockade impairs lamellipodia formation and maintenance, as well as GBM cell migration. In conclusion, the functional expression of the NCX in the lamellipodia of GBM cells at the migrating front is a conditio sine qua non for the invasion strategy of these malignant cells and thus represents a potential target for brain tumor treatment.
Topics: Humans; Glioblastoma; Sodium-Calcium Exchanger; Endothelial Cells; Cell Movement; Brain
PubMed: 37628853
DOI: 10.3390/ijms241612673