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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 -
Nedd4-2-dependent regulation of astrocytic Kir4.1 and Connexin43 controls neuronal network activity.The Journal of Cell Biology Jan 2024Nedd4-2 is an E3 ubiquitin ligase in which missense mutation is related to familial epilepsy, indicating its critical role in regulating neuronal network activity....
Nedd4-2 is an E3 ubiquitin ligase in which missense mutation is related to familial epilepsy, indicating its critical role in regulating neuronal network activity. However, Nedd4-2 substrates involved in neuronal network function have yet to be identified. Using mouse lines lacking Nedd4-1 and Nedd4-2, we identified astrocytic channel proteins inwardly rectifying K+ channel 4.1 (Kir4.1) and Connexin43 as Nedd4-2 substrates. We found that the expression of Kir4.1 and Connexin43 is increased upon conditional deletion of Nedd4-2 in astrocytes, leading to an elevation of astrocytic membrane ion permeability and gap junction activity, with a consequent reduction of γ-oscillatory neuronal network activity. Interestingly, our biochemical data demonstrate that missense mutations found in familial epileptic patients produce gain-of-function of the Nedd4-2 gene product. Our data reveal a process of coordinated astrocytic ion channel proteostasis that controls astrocyte function and astrocyte-dependent neuronal network activity and elucidate a potential mechanism by which aberrant Nedd4-2 function leads to epilepsy.
Topics: Animals; Humans; Mice; Astrocytes; Cell Membrane Permeability; Connexin 43; Mutation, Missense; Proteostasis; Potassium Channels, Inwardly Rectifying; Nedd4 Ubiquitin Protein Ligases; Epilepsy
PubMed: 38032389
DOI: 10.1083/jcb.201902050 -
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 -
Oncology Reports Oct 2023Hepatocellular carcinoma (HCC) poses a serious health burden worldwide. It is often not diagnosed until the patient is at an advanced stage of the disease, when... (Review)
Review
Hepatocellular carcinoma (HCC) poses a serious health burden worldwide. It is often not diagnosed until the patient is at an advanced stage of the disease, when treatment options are limited and the prognosis is poor. Therefore, novel treatment strategies are urgently required. Potassium (K) channels have an important role in HCC, including regulating the proliferation, migration, invasion and drug resistance of HCC cells. The aim of the present review was therefore to survey the relevant publications that have investigated K channels not only as markers for the early diagnosis of HCC, but also as potential therapeutic targets for the treatment of HCC. Several of these channels have been indicated to be the sites of action for natural products previously known to inhibit HCC; however, more systematic studies are required to determine which K channels may be utilized for the clinical treatment of HCC, particularly in the advanced stages of the disease and in cases where patients are resistant to the existing drugs.
Topics: Humans; Carcinoma, Hepatocellular; Potassium Channels; Liver Neoplasms; Biological Products; Cell Line
PubMed: 37654193
DOI: 10.3892/or.2023.8622 -
Frontiers in Physiology 2024The KCNQ family is comprised of five genes and the expression products form voltage-gated potassium channels (Kv7.1-7.5) that have a major impact upon cellular... (Review)
Review
The KCNQ family is comprised of five genes and the expression products form voltage-gated potassium channels (Kv7.1-7.5) that have a major impact upon cellular physiology in many cell types. Each functional Kv7 channel forms as a tetramer that often associates with proteins encoded by the KCNE gene family (KCNE1-5) and is critically reliant upon binding of phosphatidylinositol bisphosphate (PIP) and calmodulin. Other modulators like A-kinase anchoring proteins, ubiquitin ligases and Ca-calmodulin kinase II alter Kv7 channel function and trafficking in an isoform specific manner. It has now been identified that for Kv7.4, G protein βγ subunits (Gβγ) can be added to the list of key regulators and is paramount for channel activity. This article provides an overview of this nascent field of research, highlighting themes and directions for future study.
PubMed: 38655029
DOI: 10.3389/fphys.2024.1382904 -
Mechanisms of Ageing and Development Oct 2023A limited number of studies have shown functional changes in mitochondrial ion channels in aging and senescent cells. We have identified, for the first time,...
A limited number of studies have shown functional changes in mitochondrial ion channels in aging and senescent cells. We have identified, for the first time, mitochondrial large-conductance calcium-regulated potassium channels in human smooth muscle mitochondria. This channel, with a conductance of 273 pS, was regulated by calcium ions and membrane potential. Additionally, it was activated by the potassium channel opener NS11021 and blocked by paxilline. Importantly, we have shown that senescence of these cells induced by hydrogen peroxide treatment leads to the disappearance of potassium channel protein levels and channel activity measured by the single channel patch-clamp technique. Our data suggest that disturbances in the expression of mitochondrial large conductance calcium-regulated potassium channels may be hallmarks of cellular senescence and contribute to the misregulation of mitochondrial function in senescent cells.
Topics: Humans; Calcium; Large-Conductance Calcium-Activated Potassium Channels; Calcium Channels; Muscle, Smooth, Vascular; Potassium; Membrane Potential, Mitochondrial; Mitochondria
PubMed: 37689317
DOI: 10.1016/j.mad.2023.111871 -
BioMed Research International 2023The Kir4.1 channel, an inwardly rectifying potassium ion (K) channel, is located in the hair cells of the organ of Corti as well as the intermediate cells of the stria...
The Kir4.1 channel, an inwardly rectifying potassium ion (K) channel, is located in the hair cells of the organ of Corti as well as the intermediate cells of the stria vascularis. The Kir4.1 channel has a crucial role in the generation of endolymphatic potential and maintenance of the resting membrane potential. However, the role and functions of the Kir4.1 channel in the progenitor remain undescribed. To observe the role of Kir4.1 in the progenitor treated with the one-shot ototoxic drugs (kanamycin and furosemide), we set the proper condition in culturing Immortomouse-derived HEI-OC1 cells to express the potassium-related channels well. And also, that was reproduced in mice experiments to show the important role of Kir4.1 in the survival of hair cells after treating the ototoxicity drugs. In our results, when kanamycin and furosemide drugs were cotreated with HEI-OC1 cells, the Kir4.1 channel did not change, but the expression levels of the NKCC1 cotransporter and KCNQ4 channel are decreased. This shows that inward and outward channels were blocked by the two drugs (kanamycin and furosemide). However, noteworthy here is that the expression level of Kir4.1 channel increased when kanamycin was treated alone. This shows that Kir4.1, an inwardly rectifying potassium channel, acts as an outward channel in place of the corresponding channel when the KCNQ4 channel, an outward channel, is blocked. These results suggest that the Kir4.1 channel has a role in maintaining K homeostasis in supporting cells, with K concentration compensator when the NKCC1 cotransporter and Kv7.4 (KCNQ4) channels are deficient.
Topics: Mice; Animals; Potassium Channels, Inwardly Rectifying; Aminoglycosides; Ototoxicity; Solute Carrier Family 12, Member 2; Furosemide; Anti-Bacterial Agents; Kanamycin; Potassium; Hair
PubMed: 38143588
DOI: 10.1155/2023/4191999 -
Neural Regeneration Research Nov 2023Ion channels modulate cellular excitability by regulating ionic fluxes across biological membranes. Pathogenic mutations in ion channel genes give rise to epileptic...
Ion channels modulate cellular excitability by regulating ionic fluxes across biological membranes. Pathogenic mutations in ion channel genes give rise to epileptic disorders that are among the most frequent neurological diseases affecting millions of individuals worldwide. Epilepsies are triggered by an imbalance between excitatory and inhibitory conductances. However, pathogenic mutations in the same allele can give rise to loss-of-function and/or gain-of-function variants, all able to trigger epilepsy. Furthermore, certain alleles are associated with brain malformations even in the absence of a clear electrical phenotype. This body of evidence argues that the underlying epileptogenic mechanisms of ion channels are more diverse than originally thought. Studies focusing on ion channels in prenatal cortical development have shed light on this apparent paradox. The picture that emerges is that ion channels play crucial roles in landmark neurodevelopmental processes, including neuronal migration, neurite outgrowth, and synapse formation. Thus, pathogenic channel mutants can not only cause epileptic disorders by altering excitability, but further, by inducing morphological and synaptic abnormalities that are initiated during neocortex formation and may persist into the adult brain.
PubMed: 37282454
DOI: 10.4103/1673-5374.371347 -
Channels (Austin, Tex.) Dec 2023Inward rectifier potassium channels (Kir channels) exist in a variety of cells and are involved in maintaining resting membrane potential and signal transduction in most... (Review)
Review
Inward rectifier potassium channels (Kir channels) exist in a variety of cells and are involved in maintaining resting membrane potential and signal transduction in most cells, as well as connecting metabolism and membrane excitability of body cells. It is closely related to normal physiological functions of body and the occurrence and development of some diseases. Although the functional expression of Kir channels and their role in disease have been studied, they have not been fully elucidated. In this paper, the functional expression of Kir channels in vascular endothelial cells and smooth muscle cells and their changes in disease states were reviewed, especially the recent research progress of Kir channels in stem cells was introduced, in order to have a deeper understanding of Kir channels in vascular tissues and provide new ideas and directions for the treatment of related ion channel diseases.
Topics: Endothelial Cells; Potassium Channels, Inwardly Rectifying; Membrane Potentials; Cell Membrane; Myocytes, Smooth Muscle; Potassium
PubMed: 37463317
DOI: 10.1080/19336950.2023.2237303