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The Role of Ion Channels and Transporters in Human Health and Diseases

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: 31 December 2024 | Viewed by 11558

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Dr. Teresa Soda

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Department of Health Science, Laboratory of Physiology and Neuropharmacology, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
Interests: synaptic plasticity; NMDAreceptor; autism; endothelial cell; neurovascular coupling; Ca²⁺ signaling; nitric oxide

Special Issue Information

Dear Colleagues,

The human body relies on a delicate balance of various elements, including the precise movement of ions, electrically charged atoms, or molecules, across cell membranes. This critical task requires two crucial players: ion channels and transporters. An intricate network of membrane proteins orchestrates the flow of ions, dictating their entry and exit from cells and their release or sequestration by endogenous organelles. This meticulously controlled movement underpins numerous physiological processes, forming the very foundation of human health. Ion channels act as selective pores, opening and closing in response to various stimuli like voltage changes or the presence of specific molecules. They allow specific ions, like sodium, potassium, chloride, and calcium, to pass through the membrane, generating electrical signals and enabling communication within and between cells. In addition, water channels, known as aquaporin, are pivotal to fine-tune cellular volume during osmotic challenges. On the other hand, transporters actively move ions and solutes according to or against their concentration gradient, ensuring their proper distribution and controlling their concentration within cells. This precise control is vital for maintaining homeostasis, the stable internal environment required for cellular function. Transporters also play a key role in nutrient absorption, facilitating the uptake of essential molecules from the gut into the bloodstream for distribution throughout the body. The importance of ion channels and transporters cannot be overstated. Their proper function is vital for countless physiological processes, including synaptic transmission and plasticity, muscle contraction, fluid balance, secretion, and absorption. When these proteins malfunction, it can lead to a cascade of consequences, disrupting the delicate cellular equilibrium and causing various illnesses. Therefore, understanding the intricacies of ion channels and transporters is critical for comprehending human health and disease. The following sections will explore the specific roles these proteins play in various diseases and the potential for therapeutic interventions based on this knowledge.

I am pleased to invite you to participate in this Special Issue. Experimental papers and up-to-date review articles are all welcome.

Dr. Teresa Soda
Guest Editor

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Keywords

ion channels
transporters
ion pumps
voltage-gated channels
ionotropic receptors
TRP channels
store-operated channels
Piezo channels
NALCN channels
inositol-1,4,5-receptors
ryanodine receptors
two-pore channels
synaptic transmission
channelopathies
neurodegenerative disorders
cardiovascular disorders

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Research

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16 pages, 1838 KiB

Open AccessArticle

SGLT-2 Inhibitors’ and GLP-1 Receptor Agonists’ Influence on Neuronal and Glial Damage in Experimental Stroke

by Anna Murasheva, Oksana Fuks, Natalya Timkina, Arina Mikhailova, Timur Vlasov, Konstantin Samochernykh and Tatiana Karonova

Biomedicines 2024, 12(12), 2797; https://doi.org/10.3390/biomedicines12122797 - 10 Dec 2024

Viewed by 370

Abstract

Background: SGLT-2 inhibitors (SGLT-2i) and GLP-1 receptor agonists (GLP-1RA) have demonstrated nephro- and cardioprotective effects, but their neuroprotective properties, especially concerning stroke severity, and mechanisms are not unambiguous. We aimed to study the influence of SGLT-2i with different selectivity and GLP-1RA on brain damage volume and neurological status in non-diabetic and diabetic rats and to investigate the underlying mechanisms. Methods: Non-diabetic Wistar rats were divided into five groups (n = 10 each) and received empagliflozin, canagliflozin, or dulaglutide as study drugs and metformin as comparison drug. Control animals were administered 0.9% NaCl for 7 days before stroke. At 48 h after stroke, we assessed neurological deficit, neuronal and astroglial damage markers, and brain damage volume. We also modeled type 2 DM in Wistar rats using the high-fat diet+nicotinamide/streptozotocin method and established similar treatment groups. After 8 weeks, rats were subjected to stroke with further neurological deficit, neuroglial damage markers, and brain necrosis volume measurement. Results: In non-diabetic rats, all the drugs showed an infarct-limiting effect; SGLT-2i and dulaglutide were more effective than metformin. DULA improved neurological status compared with MET and SGLT-2i treatment. All the drugs decreased neurofilament light chains (NLCs) level and neuronal damage markers, but none of them decreased the glial damage marker S100BB. In DM, similarly, all the drugs had infarct-limiting effects. Neurological deficit was most pronounced in the untreated diabetic rats and was reduced by all study drugs. All the drugs reduced NLC level; dulaglutide and empagliflozin, but not canagliflozin, also decreased S100BB. None of the drugs affected neuron-specific enolase. Conclusions: SGLT-2i and GLP-1RA are neuroprotective in experimental stroke. GLP-1RA might be more effective than SGLT-2i as in non-diabetic conditions it influences both brain damage volume and neurological status. All study drugs decrease neuronal damage, while GLP-1RA and highly selective SGLT-2i EMPA, but not low-selective CANA, also have an impact on neuroglia in diabetic conditions. Full article

(This article belongs to the Special Issue The Role of Ion Channels and Transporters in Human Health and Diseases)

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19 pages, 4438 KiB

Open AccessArticle

The Functional Interaction of KATP and BK Channels with Aquaporin-4 in the U87 Glioblastoma Cell

by Fatima Maqoud, Laura Simone, Domenico Tricarico, Giulia Maria Camerino, Marina Antonacci and Grazia Paola Nicchia

Biomedicines 2024, 12(8), 1891; https://doi.org/10.3390/biomedicines12081891 - 19 Aug 2024

Viewed by 3759

Abstract

K⁺ channels do play a role in cell shape changes observed during cell proliferation and apoptosis. Research suggested that the dynamics of the aggregation of Aquaporin-4 (AQP4) into AQP4-OAP isoforms can trigger cell shape changes in malignant glioma cells. Here, we investigated the relationship between AQP4 and some K⁺ channels in the malignant glioma U87 line. The U87 cells transfected with the human M1-AQP4 and M23-AQP4 isoforms were investigated for morphology, the gene expression of KCNJ8, KCNJ11, ABCC8, ABCC9, KCNMA1, and Cyclin genes by RT-PCR, recording the whole-cell K⁺ ion currents by patch-clamp experiments. AQP4 aggregation into OAPs increases the plasma membrane functional expression of the Kir6.2 and SUR2 subunits of the KATP channels and of the KCNMA1 of the BK channels in U87 cells leading to a large increase in inward and outward K⁺ ion currents. These changes were associated with changes in morphology, with a decrease in cell volume in the U87 cells and an increase in the ER density. These U87 cells accumulate in the mitotic and G2 cell cycle. The KATP channel blocker zoledronic acid reduced cell proliferation in both M23 AQP4-OAP and M1 AQP4-tetramer-transfected cells, leading to early and late apoptosis, respectively. The BK channel sustains the efflux of K⁺ ions associated with the M23 AQP4-OAP expression in the U87 cells, but it is downregulated in the M1 AQP4-tetramer cells. The KATP channels are effective in the M1 AQP4-tetramer and M23 AQP4-OAP cells. Zoledronic acid can be effective in targeting pathogenic M1 AQP4-tetramer cell phenotypes inhibiting KATP channels and inducing early apoptosis. Full article

(This article belongs to the Special Issue The Role of Ion Channels and Transporters in Human Health and Diseases)

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Figure 1

Figure 1
Expression of AQP4 in U87 cells. (A) Epifluorescence images of U87wt and U87 expressing M1 AQP4-tetramers or M23 AQP4-OAPs. AQP4 staining is shown in red and DAPI in blue. Scale bar 20 μm. (B) Immunoblot detection of AQP4 expression levels in U87 cells transfected with M1-AQP4 (AQP4-tetramers) and M23-AQP4 (AQP4-OAPs). GFAP and GAPDH were used to normalize for equal loading. Full article ">Figure 2
Characterization of inward and outward macroscopic K+ ion currents recorded in U87wt cells. The currents were recorded using a whole cell configuration under physiological concentration of K+ ions in the bath and pipette and were obtained in response to voltage pulses from −120 to +120 mV in increments of 20 mV, starting at HP = −60 mV (Vm) and intracellular-free Ca2+ ions (1.6 × 10−6 M). (A) TEA (5 × 10−3 M) suppressed the outward K+ ion currents, and TEA/Ba2+ (5 × 10−3 M) fully suppressed also the inward K+ ion currents. (B) The selective BK channel blocker IbTX (4 × 10−7 M) reduced the outward K+ ion currents that were fully reduced by TEA (5 × 10−3 M). (C) KATP currents recorded in U87wt cells in low intracellular ATP 1 × 10−3 M. Glibenclamide (5 × 10−8 M) suppressed the inward currents, suggesting the presence of KATP channels in the cells. Cells of the same size were selected for patch-clamp experiments. Each point represented the mean ± SEM (N patches = 10–15). (D) Percentage of blocking of K+ ion currents in the presence of the antagonists with respect to the control condition at 60 mV and −60 mV (Vm). Full article ">Figure 3
Effects of antagonists and agonists of the K+ channels on the proliferation of U87wt cells. * p < 0.05 and ** p < 0.01 when compared to the experimental group not treated after 48 h of incubation. Each point represented the mean ± SEM. Full article ">Figure 4
Characterization of macroscopic inward and outward K+ ion currents recorded in U87wt cells and after transfection with M1 AQP4-tetramer or M23 AQP4-OAP. Whole cell currents were recorded under physiological concentration of K+ ions in the bath and pipette and were obtained in response to voltage pulses from −120 to +120 mV in 20 mV increments, starting at HP = −60 mV (Vm). (A) Macroscopic K+ ion currents recorded in AQP4-OAP-transfected U87 cells. The presence of AQP4-OAPs caused a significant increase in the inward and outward currents that were reduced by TEA and BaCl2. (B) Macroscopic K+ ion currents recorded in AQP4-tetramer-transfected U87 cells. The presence of M1 AQP4-tetramers caused a significant increase in the inward currents; however, the outward K+ ion currents were reduced in the amplitude. (C) The presence of M23 AQP4-OAPs caused a large increase in the currents at negative and positive membrane potentials vs. not transfected cell. Instead, the presence of AQP4-tetramers led to an increase in the currents at negative membrane potentials; conversely, the outward K+ ion currents decreased at positive membrane potentials. Data were pooled from N patches = 10–12. (D) Percentage of reduction in the K+ ion currents in the presence of the antagonist TEA with respect to the control condition at 60 mV and −60 mV (Vm). Each point represents the mean ± SEM. Full article ">Figure 5
Expression profile of KCNMA1, KCNJ11, KCNJ8, ABCC8, ABCC9, and TRPV1 genes in U87 glioma cells in the presence of the malignant M1 AQP4-tetramer and M23 AQP4-OAP aggregation vs. wt condition. * p < 0.05 when compared to the experimental group not treated (WT) after 48 h of incubation. Each point represented the mean ± SEM. Full article ">Figure 6
Effect of pharmacological inhibition of the Kir6.2-SUR2 channel activity with zoledronic acid on AQP4s expressing U87 cells. (A) Epifluorescence images of U87 cells expressing AQP4-tetramers or AQP4-OAPs treated with diazoxide or zoledronic acid. AQP4 staining is shown in red, and DAPI for nuclear staining is in blue. Phalloidin (in green) was used to visualize F-actin. The white arrowheads indicate the round-shaped cells, the arrows indicate irregular-shaped cells, and the blue arrowheads indicate the apoptotic beads. Scale bar 100 μm. ((B) top) Drawing/diagram showing the morphological change of U87 cells expressing AQP4-OAPs after pharmacological treatment with zoledronic acid according Coffin hypothesis and relative epifluorescence images. ((B) bottom) Epifluorescence images of U87 expressing AQP4-OAPs treated with zoledronic, showing the irregular-shaped cell, the round-shaped cell, and the apoptosis. AQP4 staining is shown in red. Phalloidin (in green) was used to visualize F-actin. Scale bar 10 µm. A histogram was created to display the percentage of round-shaped cells per field in U87 cells and those expressing AQP4-OAPs after treatment under different conditions. The conditions include treatment with zoledronic acid (an inhibitor), control conditions (vehicle), and diazoxide (an agonist). The histogram compares these percentages across the different treatment groups, highlighting the effects of the inhibitor and agonist on cell morphology. Values are expressed as mean ± SEM of percentage of cells with altered cell morphology out of the total number of transfected cells per field. ** p < 0.005; ((C) top) Representative image of expressing AQP4-OAPs in control condition or after treatment with zoledronic or diazoxide as indicated and stained with DAPI to visualize nuclei. Scale bar 50 µm. ((C) bottom) Dot plot showing the analysis of % of condensed nuclei for field and the nuclear area of images in A. Values are expressed in µm2 and represent mean ± SEM. * p < 0.05, *** p < 0.001, n = 3, two-way ANOVA/Tukey’s tests. Full article ">Figure 7
RT PCR expression of the cyclin genes (E, A, and B1) in the U87 cells following M23 AQP4-OAP transfection. * p < 0.05 when compared to the experimental group not treated (WT) after 48 h of incubation. • represent the average of each single experiment. Each point represented the mean of at least three experiments± SEM. Full article ">

13 pages, 3173 KiB

Open AccessArticle

Chronic Mexiletine Administration Increases Sodium Current in Non-Diseased Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

by Giovanna Nasilli, Arie O. Verkerk, Molly O’Reilly, Loukia Yiangou, Richard P. Davis, Simona Casini and Carol Ann Remme

Biomedicines 2024, 12(6), 1212; https://doi.org/10.3390/biomedicines12061212 - 29 May 2024

Cited by 1 | Viewed by 1499

Abstract

A sodium current (I_Na) reduction occurs in the setting of many acquired and inherited conditions and is associated with cardiac conduction slowing and increased arrhythmia risks. The sodium channel blocker mexiletine has been shown to restore the trafficking of mutant sodium channels to the membrane. However, these studies were mostly performed in heterologous expression systems using high mexiletine concentrations. Moreover, the chronic effects on I_Na in a non-diseased cardiomyocyte environment remain unknown. In this paper, we investigated the chronic and acute effects of a therapeutic dose of mexiletine on I_Na and the action potential (AP) characteristics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) of a healthy individual. Control hiPSC-CMs were incubated for 48 h with 10 µM mexiletine or vehicle. Following the wash-out of mexiletine, patch clamp analysis and immunocytochemistry experiments were performed. The incubation of hiPSC-CMs for 48 h with mexiletine (followed by wash-out) induced a significant increase in peak I_Na of ~75%, without any significant change in the voltage dependence of (in)activation. This was accompanied by a significant increase in AP upstroke velocity, without changes in other AP parameters. The immunocytochemistry experiments showed a significant increase in membrane Na_v1.5 fluorescence following a 48 h incubation with mexiletine. The acute re-exposure of hiPSC-CMs to 10 µM mexiletine resulted in a small but significant increase in AP duration, without changes in AP upstroke velocity, peak I_Na density, or the I_Na voltage dependence of (in)activation. Importantly, the increase in the peak I_Na density and resulting AP upstroke velocity induced by chronic mexiletine incubation was not counteracted by the acute re-administration of the drug. In conclusion, the chronic administration of a clinically relevant concentration of mexiletine increases I_Na density in non-diseased hiPSC-CMs, likely by enhancing the membrane trafficking of sodium channels. Our findings identify mexiletine as a potential therapeutic strategy to enhance and/or restore I_Na and cardiac conduction. Full article

(This article belongs to the Special Issue The Role of Ion Channels and Transporters in Human Health and Diseases)

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Figure 1

Figure 1
Incubation of hiPSC-CMs for 48 h with 10 µM mexiletine increases INa density. (A) Schematic representation of the experimental approach. (B) Representative INa traces for hiPSC-CMs recorded after a 48 h incubation with the vehicle or mexiletine (10 µM). Average current-voltage relationships in hiPSC-CMs (C) and voltage dependence of activation (D) and inactivation (E). Insets: voltage clamp protocols; n, number of cells; * p < 0.05, two-way RM ANOVA followed by a Holm-Sidak test for post hoc analysis. Full article ">Figure 2
Immunostaining of hiPSC-CMs treated with vehicle or 10 µM mexiletine for 48 h. (A) Example images of hiPSC-CMs stained for DAPI (blue), α-actinin (red), and NaV1.5 (green). (B) Quantification of NaV1.5 membrane fluorescence intensity. Scale bar is 25 µm; n represents the number of cells analyzed. * p < 0.05, unpaired Student’s t-test. Full article ">Figure 3
Acute effect of mexiletine on INa density and INa voltage dependence of (in)activation in hiPSC-CMs. (A) Schematic representation of the experimental approach. (B,C) Average sodium current-voltage relationships of hiPSC-CMs (previously incubated for 48 h with the vehicle (B), or mexiletine (C)) at baseline and after the acute (re-)administration (5 min) of 10 µM mexiletine. (D–G) Voltage dependence of activation (D,E) and inactivation (F,G) measured in hiPSC-CMs (previously incubated for 48 h with the vehicle (D,F), or mexiletine (E,G)) at baseline and after the acute (re-)administration (5 min) of 10 µM mexiletine. Insets: voltage clamp protocols; n, number of cells. V1/2 and slope factor k values are listed in <a href="#biomedicines-12-01212-t002" class="html-table">Table 2</a>. Full article ">Figure 4
Incubation of hiPSC-CMs for 48 h with 10 µM mexiletine increases action potential upstroke velocity without affecting repolarization. (A) Schematic representation of the experimental approach. (B) Representative action potential (AP) traces of hiPSC-CMs incubated for 48 h with the vehicle or mexiletine (10 µM). Insets: first derivative of the AP upstroke. (C) Average values for the AP upstroke velocity (Vmax), AP amplitude (APA), resting membrane potential (RMP), and AP duration at 20%, 50% and 90% repolarization (APD20, APD50, and APD90, respectively), measured at a pacing frequency of 1 Hz. n, number of cells. * p < 0.05, unpaired Student’s t-test. Full article ">Figure 5
Acute effect of mexiletine on action potential properties in hiPSC-CMs. (A) Schematic representation of the experimental approach. (B) Average data for the maximal upstroke velocity (Vmax), AP amplitude (APA), resting membrane potential (RMP), AP duration at 20%, 50%, and 90% repolarization (APD20, APD50, and APD90, respectively) in hiPSC-CMs after a 48 h incubation with the vehicle (baseline), after 5 min of the acute administration of 10 µM mexiletine (wash-in), and after the wash-out of the drug. (C) Average data for Vmax, APA, RMP, APD20, APD50, and APD90 in hiPSC-CMs after a 48 h incubation with 10 µM mexiletine (baseline), after 5 min of the acute re-administration of 10 µM mexiletine (wash-in), and after wash-out. n, number of cells; * p < 0.05, one-way RM ANOVA followed by a Holm-Sidak test for post hoc analysis or a one-way RM ANOVA on Ranks (Friedman test) followed by Tukey’s test for post hoc analysis when the data were not normally distributed. Full article ">

Review

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29 pages, 3011 KiB

Open AccessReview

Sodium Chloride Cotransporter in Hypertension

by Annalisa Castagna, Gabriele Mango, Nicola Martinelli, Luigi Marzano, Sara Moruzzi, Simonetta Friso and Francesca Pizzolo

Biomedicines 2024, 12(11), 2580; https://doi.org/10.3390/biomedicines12112580 - 11 Nov 2024

Viewed by 1444

Abstract

The sodium chloride cotransporter (NCC) is essential for electrolyte balance, blood pressure regulation, and pathophysiology of hypertension as it mediates the reabsorption of ultrafiltered sodium in the renal distal convoluted tubule. Given its pivotal role in the maintenance of extracellular fluid volume, the NCC is regulated by a complex network of cellular pathways, which eventually results in either its phosphorylation, enhancing sodium and chloride ion absorption from urines, or dephosphorylation and ubiquitination, which conversely decrease NCC activity. Several factors could influence NCC function, including genetic alterations, hormonal stimuli, and pharmacological treatments. The NCC’s central role is also highlighted by several abnormalities resulting from genetic mutations in its gene and consequently in its structure, leading to dysregulation of blood pressure control. In the last decade, among other improvements, the acquisition of knowledge on the NCC and other renal ion channels has been favored by studies on extracellular vesicles (EVs). Dietary sodium and potassium intake are also implicated in the tuning of NCC activity. In this narrative review, we present the main cornerstones and recent evidence related to NCC control, focusing on the context of blood pressure pathophysiology, and promising new therapeutical approaches. Full article

(This article belongs to the Special Issue The Role of Ion Channels and Transporters in Human Health and Diseases)

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Graphical abstract

Graphical abstract
Full article ">Figure 1
Sodium reabsorption along the nephron. Most of the sodium reabsorption occurs in the proximal tubule (pink) via NHE3, which mediates about 70% of the Na+ transport, followed by NKCC2 in the thick ascending limb (green), which is responsible for 25%. About 5% of Na+ reabsorption occurs in the distal tubule, which includes the distal convoluted tubule (purple) and the collecting duct (magenta). The NCC is located only in the proximal part of the distal convoluted tubule, while ENaC is present in both distal convoluted tubule and collecting duct. A representation of the NCC dimeric structure is also illustrated in the blow-up. Figure created in <a href="http://BioRender.com" target="_blank">BioRender.com</a> [<a href="#B6-biomedicines-12-02580" class="html-bibr">6</a>]. Full article ">Figure 2
Three-dimensional structure of the NCC dimer embedded in the apical cell membrane. This schematic representation highlights the functional domains of the transporter: (1) the extracellular domain (green); (2) the transmembrane domain (red); and (3) the cytosolic domain (blue). A close-up of one ion binding pocket, located within the transmembrane domain, shows three binding sites: one for Na+ (magenta); one for Cl− (cyan); and one for polythiazide, a thiazide diuretic (yellow). The representation is based on the structural prediction provided by the Orientations of Proteins in Membranes (OPM) database [<a href="#B22-biomedicines-12-02580" class="html-bibr">22</a>] of the NCC inward-facing conformation obtained by Fan et al. [<a href="#B20-biomedicines-12-02580" class="html-bibr">20</a>] (PDB ID: 8FHO). PyMOL (Schrödinger, LLC) was used to visualize the structure and generate the image. Figure created in <a href="http://BioRender.com" target="_blank">BioRender.com</a> [<a href="#B6-biomedicines-12-02580" class="html-bibr">6</a>]. Full article ">Figure 3
Post-translational modifications regulating NCC activity in the DCT. NCC phosphorylation (yellow) is primarily mediated by the WNK-SPAK/OSR1 kinase cascade. WNK1 and WNK4 (with-no-lysine kinases) activate SPAK (STE20/SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-response protein 1), which, in turn, phosphorylate the NCC, increasing its transport activity in the apical membrane. WNK autophosphorylation is stimulated by low Cl− intracellular levels, which result from a decrease in K+ intracellular concentration. These changes are, respectively, mediated by basolateral chlorine (light blue) and potassium channels (pink). Cab39 (calcium binding protein 39) is another regulator of NCC phosphorylation since it is required for SPAK activation. NCC dephosphorylation (red) leads to a reduction in its activity and is carried out by protein phosphatases PP1, PP3, and PP4. PP1 is regulated by protein phosphatase 1 inhibitor-1 (I-1) through the cAMP/PKA pathway. A rise in cAMP levels activates PKA (protein kinase A), which phosphorylates I-1, preventing PP1 from dephosphorylating the NCC. Ubiquitination (purple) is another key regulatory mechanism that affects NCC function. WNK abundance is controlled by an E3 ubiquitin ligase complex composed of KLHL3 (Kelch-like protein 3) and CUL3 (Cullin 3). This complex tags the NCC with ubiquitin (Ub), marking it for proteasomal degradation. KLHL3 acts as adapter for WNK, and its phosphorylation prevents this binding. PP3 is responsible for KLHL3 activation through dephosphorylation. Additionally, NEDD4-2, another ubiquitin ligase, directly mediates NCC degradation through ubiquitination. Figure created in <a href="http://BioRender.com" target="_blank">BioRender.com</a> [<a href="#B6-biomedicines-12-02580" class="html-bibr">6</a>]. Full article ">Figure 4
Physiological stimuli that modulate NCC activity. The key signaling pathways involved in NCC regulation by various hormones are illustrated. Arginine vasopressin (AVP, blue) binds to the V2 receptor (V2R) on the basolateral membrane, activating adenylate cyclase 6 (AC6), which increases cyclic AMP (cAMP) levels. Elevated cAMP stimulates protein kinase A (PKA), leading to: (a) stimulation of WNK-SPAK/OSR1-NCC cascade through WNK kinase phosphorylation; (b) inhibition of protein phosphatase 1 (PP1) by phosphorylating its inhibitor, I-1, maintaining the phosphorylated state of the NCC; (c) phosphorylation and inactivation of Kelch-like protein 3 (KLHL3), diminishing WNK ubiquitination and consequent degradation. Aldosterone (ALDO, orange) enhances the NCC in both a mineralocorticoid receptor (MR)-dependent and MR-independent manner. Binding to MR, it could stimulate serum- and glucocorticoid-regulated kinase 1 (SGK1), which activates WNKs and simultaneously inhibits NEDD4-2-mediated ubiquitination. On the other hand, aldosterone stimulates ENaC-mediated potassium secretion, eventually inducing hypokalemia. Low extracellular K+ levels are sensed by DCT cells through Kir4.1/Kir5.1 K+ channels, which, once active, lead to a drop in K+ intracellular concentration, stimulating basolateral Cl− transport through ClC-Kb. A decrease in intracellular Cl− levels releases the inhibition of WNK kinases, enabling their autophosphorylation and thus stimulating WNK-SPAK/OSR1-NCC pathway. Cortisol (CORT, red) may exert the same effect as aldosterone, likely through the interaction with the glucocorticoid receptor (GR). Angiotensin II (ANGII, purple) binds to the angiotensin II type 1 receptor (AT1R), activating protein kinase C (PKC), which catalyzes both WNK and KLHL3 phosphorylation. Angiotensin II activates the NCC via AngII receptor type 1 (AT1R), stimulating the WNK4-SPAK kinase cascade and the phosphorylation of KLHL. Angiotensin II can also induce aldosterone and ENaC-mediated hypokalemia, thereby triggering potassium sensing through Kir4.1/Kir5.1 K+ channels. Insulin (INS, green) activates the phosphoinositide 3-kinase (PI3K) pathway, leading to the activation of protein kinase B (AKT). AKT stimulates NCC activity through the phosphorylation of both WNK kinases and KLHL3. Figure created in <a href="http://BioRender.com" target="_blank">BioRender.com</a> [<a href="#B6-biomedicines-12-02580" class="html-bibr">6</a>]. Full article ">Figure 5
Pharmacological modulation of NCC function in the DCT. Inhibitors are shown in red, while enhancers are shown in light blue. Thiazide diuretics directly inhibit NCC blocking ion translocation, while mineralocorticoid receptor antagonists (MRA) act indirectly, blocking the MR-mediated effect of aldosterone. Loop diuretics (LD) activate the NCC, increasing the amount of sodium delivered to the DCT and the secretion of aldosterone, which increases NCC activity in both an MR-dependent and an MR-independent manner. Calcineurin inhibitors (CNI) decrease PP3-mediated dephosphorylation of NCC, basolateral K+ channel, and KLHL3, thus stimulating NCC activity at various levels. Salbutamol (SALB) could activate basolateral K+ channel through a signaling pathway likely mediated by β2-adrenergic receptor. A drop in K+ intracellular concentration eventually triggers WNK-SPAK/OSR1-NCC cascade. SGLT2 inhibitors (SGLT2i, shown in purple) may influence NCC activity, increasing the delivery of glucose and fructose to the DCT and possibly stimulating a signaling pathway involving the calcium-sensing receptor (CaSR) and protein kinase C (PKC). Figure created in <a href="http://BioRender.com" target="_blank">BioRender.com</a> [<a href="#B6-biomedicines-12-02580" class="html-bibr">6</a>]. Full article ">

34 pages, 3310 KiB

Open AccessReview

Two Signaling Modes Are Better than One: Flux-Independent Signaling by Ionotropic Glutamate Receptors Is Coming of Age

by Valentina Brunetti, Teresa Soda, Roberto Berra-Romani, Giovambattista De Sarro, Germano Guerra, Giorgia Scarpellino and Francesco Moccia

Biomedicines 2024, 12(4), 880; https://doi.org/10.3390/biomedicines12040880 - 16 Apr 2024

Cited by 3 | Viewed by 1620

Abstract

Glutamate is the major excitatory neurotransmitter in the central nervous system. Glutamatergic transmission can be mediated by ionotropic glutamate receptors (iGluRs), which mediate rapid synaptic depolarization that can be associated with Ca²⁺ entry and activity-dependent change in the strength of synaptic transmission, as well as by metabotropic glutamate receptors (mGluRs), which mediate slower postsynaptic responses through the recruitment of second messenger systems. A wealth of evidence reported over the last three decades has shown that this dogmatic subdivision between iGluRs and mGluRs may not reflect the actual physiological signaling mode of the iGluRs, i.e., α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid (AMPA) receptors (AMPAR), kainate receptors (KARs), and N-methyl-D-aspartate (NMDA) receptors (NMDARs). Herein, we review the evidence available supporting the notion that the canonical iGluRs can recruit flux-independent signaling pathways not only in neurons, but also in brain astrocytes and cerebrovascular endothelial cells. Understanding the signaling versatility of iGluRs can exert a profound impact on our understanding of glutamatergic synapses. Furthermore, it may shed light on novel neuroprotective strategies against brain disorders. Full article

(This article belongs to the Special Issue The Role of Ion Channels and Transporters in Human Health and Diseases)

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Transporters, Ion Channels, and Junctional Proteins in Choroid Plexus Epithelial Cells

by Masaki Ueno, Yoichi Chiba, Ryuta Murakami, Yumi Miyai, Koichi Matsumoto, Keiji Wakamatsu, Toshitaka Nakagawa, Genta Takebayashi, Naoya Uemura, Ken Yanase and Yuichi Ogino

Biomedicines 2024, 12(4), 708; https://doi.org/10.3390/biomedicines12040708 - 22 Mar 2024

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Abstract

The choroid plexus (CP) plays significant roles in secreting cerebrospinal fluid (CSF) and forming circadian rhythms. A monolayer of epithelial cells with tight and adherens junctions of CP forms the blood–CSF barrier to control the movement of substances between the blood and ventricles, as microvessels in the stroma of CP have fenestrations in endothelial cells. CP epithelial cells are equipped with several kinds of transporters and ion channels to transport nutrient substances and secrete CSF. In addition, junctional components also contribute to CSF production as well as blood–CSF barrier formation. However, it remains unclear how junctional components as well as transporters and ion channels contribute to the pathogenesis of neurodegenerative disorders. In this manuscript, recent findings regarding the distribution and significance of transporters, ion channels, and junctional proteins in CP epithelial cells are introduced, and how changes in expression of their epithelial proteins contribute to the pathophysiology of brain disorders are reviewed. Full article

(This article belongs to the Special Issue The Role of Ion Channels and Transporters in Human Health and Diseases)

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