International Journal of Molecular Sciences

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14 pages, 4133 KiB

Open AccessArticle

Disruption of the Unique ABCG-Family NBD:NBD Interface Impacts Both Drug Transport and ATP Hydrolysis

by Parth Kapoor, Deborah A. Briggs, Megan H. Cox and Ian D. Kerr

Int. J. Mol. Sci. 2020, 21(3), 759; https://doi.org/10.3390/ijms21030759 - 23 Jan 2020

Cited by 3 | Viewed by 3038

Abstract

ABCG2 is one of a triumvirate of human multidrug ATP binding cassette (ABC) transporters that are implicated in the defense of cells and tissues against cytotoxic chemicals, but these transporters can also confer chemotherapy resistance states in oncology. Understanding the mechanism of ABCG2 [...] Read more.

ABCG2 is one of a triumvirate of human multidrug ATP binding cassette (ABC) transporters that are implicated in the defense of cells and tissues against cytotoxic chemicals, but these transporters can also confer chemotherapy resistance states in oncology. Understanding the mechanism of ABCG2 is thus imperative if we are to be able to counter its deleterious activity. The structure of ABCG2 and its related family members (ABCG5/G8) demonstrated that there were two interfaces between the nucleotide binding domains (NBD). In addition to the canonical ATP “sandwich-dimer” interface, there was a second contact region between residues at the C-terminus of the NBD. We investigated this second interface by making mutations to a series of residues that are in close interaction with the opposite NBD. Mutated ABCG2 isoforms were expressed in human embryonic kidney (HEK) 293T cells and analysed for targeting to the membrane, drug transport, and ATPase activity. Mutations to this second interface had a number of effects on ABCG2, including altered drug specificity, altered drug transport, and, in two mutants, a loss of ATPase activity. The results demonstrate that this region is particularly sensitive to mutation and can impact not only direct, local NBD events (i.e., ATP hydrolysis) but also the allosteric communication to the transmembrane domains and drug transport. Full article

(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)

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13 pages, 1654 KiB

Open AccessArticle

Aquaglyceroporins Are Differentially Expressed in Beige and White Adipocytes

by Inês Vieira da Silva, Francisco Díaz-Sáez, António Zorzano, Anna Gumà, Marta Camps and Graça Soveral

Int. J. Mol. Sci. 2020, 21(2), 610; https://doi.org/10.3390/ijms21020610 - 17 Jan 2020

Cited by 17 | Viewed by 3569

Abstract

Browning of white adipocytes has been proposed as a powerful strategy to overcome metabolic complications, since brown adipocytes are more catabolic, expending energy as a heat form. However, the biological pathways involved in the browning process are still unclear. Aquaglyceroporins are a sub-class [...] Read more.

Browning of white adipocytes has been proposed as a powerful strategy to overcome metabolic complications, since brown adipocytes are more catabolic, expending energy as a heat form. However, the biological pathways involved in the browning process are still unclear. Aquaglyceroporins are a sub-class of aquaporin water channels that also permeate glycerol and are involved in body energy homeostasis. In the adipose tissue, aquaporin-7 (AQP7) is the most representative isoform, being crucial for white adipocyte fully differentiation and glycerol metabolism. The altered expression of AQP7 is involved in the onset of obesity and metabolic disorders. Herein, we investigated if aquaglyceroporins are implicated in beige adipocyte differentiation, similar to white cells. Thus, we optimized a protocol of murine 3T3-L1 preadipocytes browning that displayed increased beige and decreased white adipose tissue features at both gene and protein levels and evaluated aquaporin expression patterns along the differentiation process together with cellular lipid content. Our results revealed that AQP7 and aquaporin-9 (AQP9) expression was downregulated throughout beige adipocyte differentiation compared to white differentiation, which may be related to the beige physiological role of heat production from oxidative metabolism, contrasting with the anabolic/catabolic lipid metabolism requiring glycerol gateways occurring in white adipose cells. Full article

(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)

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8 pages, 1171 KiB

Open AccessArticle

Lixivaptan, a New Generation Diuretic, Counteracts Vasopressin-Induced Aquaporin-2 Trafficking and Function in Renal Collecting Duct Cells

by Annarita Di Mise, Maria Venneri, Marianna Ranieri, Mariangela Centrone, Lorenzo Pellegrini, Grazia Tamma and Giovanna Valenti

Int. J. Mol. Sci. 2020, 21(1), 183; https://doi.org/10.3390/ijms21010183 - 26 Dec 2019

Cited by 15 | Viewed by 3633

Abstract

Vasopressin V2 receptor (V2R) antagonists (vaptans) are a new generation of diuretics. Compared with classical diuretics, vaptans promote the excretion of retained body water in disorders in which plasma vasopressin concentrations are inappropriately high for any given plasma osmolality. Under these conditions, an [...] Read more.

Vasopressin V2 receptor (V2R) antagonists (vaptans) are a new generation of diuretics. Compared with classical diuretics, vaptans promote the excretion of retained body water in disorders in which plasma vasopressin concentrations are inappropriately high for any given plasma osmolality. Under these conditions, an aquaretic drug would be preferable over a conventional diuretic. The clinical efficacy of vaptans is in principle due to impaired vasopressin-regulated water reabsorption via the water channel aquaporin-2 (AQP2). Here, the effect of lixivaptan—a novel selective V2R antagonist—on the vasopressin-cAMP/PKA signaling cascade was investigated in mouse renal collecting duct cells expressing AQP2 (MCD4) and the human V2R. Compared to tolvaptan—a selective V2R antagonist indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia—lixivaptan has been predicted to be less likely to cause liver injury. In MCD4 cells, clinically relevant concentrations of lixivaptan (100 nM for 1 h) prevented dDAVP-induced increase of cytosolic cAMP levels and AQP2 phosphorylation at ser-256. Consistent with this finding, real-time fluorescence kinetic measurements demonstrated that lixivaptan prevented dDAVP-induced increase in osmotic water permeability. These data represent the first detailed demonstration of the central role of AQP2 blockade in the aquaretic effect of lixivaptan and suggest that lixivaptan has the potential to become a safe and effective therapy for the treatment of disorders characterized by high plasma vasopressin concentrations and water retention. Full article

(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)

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16 pages, 3494 KiB

Open AccessArticle

Absolute Protein Amounts and Relative Abundance of Volume-regulated Anion Channel (VRAC) LRRC8 Subunits in Cells and Tissues Revealed by Quantitative Immunoblotting

by Sumaira Pervaiz, Anja Kopp, Lisa von Kleist and Tobias Stauber

Int. J. Mol. Sci. 2019, 20(23), 5879; https://doi.org/10.3390/ijms20235879 - 23 Nov 2019

Cited by 15 | Viewed by 3954

Abstract

The volume-regulated anion channel (VRAC) plays an important role in osmotic cell volume regulation. In addition, it is involved in various physiological processes such as insulin secretion, glia-neuron communication and purinergic signaling. VRAC is formed by hetero-hexamers of members of the LRRC8 protein [...] Read more.

The volume-regulated anion channel (VRAC) plays an important role in osmotic cell volume regulation. In addition, it is involved in various physiological processes such as insulin secretion, glia-neuron communication and purinergic signaling. VRAC is formed by hetero-hexamers of members of the LRRC8 protein family, which consists of five members, LRRC8A-E. LRRC8A is an essential subunit for physiological functionality of VRAC. Its obligate heteromerization with at least one of its paralogues, LRRC8B-E, determines the biophysical properties of VRAC. Moreover, the subunit composition is of physiological relevance as it largely influences the activation mechanism and especially the substrate selectivity. However, the endogenous tissue-specific subunit composition of VRAC is unknown. We have now developed and applied a quantitative immunoblot study of the five VRAC LRRC8 subunits in various mouse cell lines and tissues, using recombinant protein for signal calibration. We found tissue-specific expression patterns of the subunits, and generally relative low expression of the essential LRRC8A subunit. Immunoprecipitation of LRRC8A also co-precipitates an excess of the other subunits, suggesting that non-LRRC8A subunits present the majority in hetero-hexamers. With this, we can estimate that in the tested cell lines, the number of VRAC channels per cell is in the order of 10,000, which is in agreement with earlier calculations from the comparison of single-channel and whole-cell currents. Full article

(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)

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17 pages, 5648 KiB

Open AccessArticle

Predictive Value of Serum Antibodies and Point Mutations of AQP4, AQP1 and MOG in A Cohort of Spanish Patients with Neuromyelitis Optica Spectrum Disorders

by Pablo García-Miranda, Francisco J. Morón-Civanto, Maria del Mar Martínez-Olivo, Nela Suárez-Luna, Reposo Ramírez-Lorca, Lucía Lebrato-Hernández, Raquel Lamas-Pérez, Guillermo Navarro, Javier Abril-Jaramillo, Maria Isabel García-Sánchez, José Luis Casado-Chocán, Antonio José Uclés-Sánchez, Mercedes Romera, Miriam Echevarría and María Díaz-Sánchez

Int. J. Mol. Sci. 2019, 20(22), 5810; https://doi.org/10.3390/ijms20225810 - 19 Nov 2019

Cited by 9 | Viewed by 5136

Abstract

The detection of IgG aquaporin-4 antibodies in the serum of patients with Neuromyelitis optica (NMO) has dramatically improved the diagnosis of this disease and its distinction from multiple sclerosis. Recently, a group of patients have been described who have an NMO spectrum disorder [...] Read more.

The detection of IgG aquaporin-4 antibodies in the serum of patients with Neuromyelitis optica (NMO) has dramatically improved the diagnosis of this disease and its distinction from multiple sclerosis. Recently, a group of patients have been described who have an NMO spectrum disorder (NMOsd) and who are seronegative for AQP4 antibodies but positive for IgG aquaporin-1 (AQP1) or myelin oligodendrocyte glycoprotein (MOG) antibodies. The purpose of this study was to determine whether AQP1 and MOG could be considered new biomarkers of this disease; and if point mutations in the gDNA of AQP4, AQP1 and MOG genes could be associated with the etiology of NMOsd. We evaluated the diagnostic capability of ELISA and cell-based assays (CBA), and analyzed their reliability, specificity, and sensitivity in detecting antibodies against these three proteins. The results showed that both assays can recognize these antigen proteins under appropriate conditions, but only anti-AQP4 antibodies, and not AQP1 or MOG, appears to be a clear biomarker for NMOsd. CBA is the best method for detecting these antibodies; and serum levels of AQP4 antibodies do not correlate with the progression of this disease. So far, the sequencing analysis has not revealed a genetic basis for the etiology of NMOsd, but a more extensive analysis is required before definitive conclusions can be drawn. Full article

(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)

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12 pages, 1345 KiB

Open AccessArticle

Tissue-Wide Gene Expression Analysis of Sodium/Phosphate Co-Transporters in Pigs

by Aisanjiang Wubuli, Henry Reyer, Eduard Muráni, Siriluck Ponsuksili, Petra Wolf, Michael Oster and Klaus Wimmers

Int. J. Mol. Sci. 2019, 20(22), 5576; https://doi.org/10.3390/ijms20225576 - 8 Nov 2019

Cited by 16 | Viewed by 4077

Abstract

Sodium/phosphate co-transporters are considered to be important mediators of phosphorus (P) homeostasis. The expression of specific sodium/phosphate co-transporters is routinely used as an immediate response to dietary interventions in different species. However, a general understanding of their tissue-specificity is required to elucidate their [...] Read more.

Sodium/phosphate co-transporters are considered to be important mediators of phosphorus (P) homeostasis. The expression of specific sodium/phosphate co-transporters is routinely used as an immediate response to dietary interventions in different species. However, a general understanding of their tissue-specificity is required to elucidate their particular contribution to P homeostasis. In this study, the tissue-wide gene expression status of all currently annotated sodium/phosphate co-transporters were investigated in two pig trials focusing on a standard commercial diet (trial 1) or divergent P-containing diets (trial 2). A wide range of tissues including the gastrointestinal tract (stomach, duodenum, jejunum, ileum, caecum, and colon), kidney, liver, bone, muscle, lung, and aorta were analyzed. Both trials showed consistent patterns in the overall tissue-specific expression of P transporters. While SLC34A2 was considered as the most important intestinal P transporter in other species including humans, SLC34A3 appeared to be the most prominent intestinal P transporter in pigs. In addition, the P transporters of the SLC17 family showed basal expression in the pig intestine and might have a contribution to P homeostasis. The expression patterns observed in the distal colon provide evidence that the large intestine may also be relevant for intestinal P absorption. A low dietary P supply induced higher expressions of SLC20A1, SLC20A2, SLC34A1, and SLC34A3 in the kidney cortex. The results suggest that the expression of genes encoding transcellular P transporters is tissue-specific and responsive to dietary P supply, while underlying regulatory mechanisms require further analyses. Full article

(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)

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20 pages, 4066 KiB

Open AccessArticle

Kinetic Models of Secondary Active Transporters

by Verena Burtscher, Klaus Schicker, Michael Freissmuth and Walter Sandtner

Int. J. Mol. Sci. 2019, 20(21), 5365; https://doi.org/10.3390/ijms20215365 - 28 Oct 2019

Cited by 18 | Viewed by 3854

Abstract

Kinetic models have been employed to understand the logic of substrate transport through transporters of the Solute Carrier (SLC) family. All SLC transporters operate according to the alternate access model, which posits that substrate transport occurs in a closed loop of partial reactions [...] Read more.

Kinetic models have been employed to understand the logic of substrate transport through transporters of the Solute Carrier (SLC) family. All SLC transporters operate according to the alternate access model, which posits that substrate transport occurs in a closed loop of partial reactions (i.e., a transport cycle). Kinetic models can help to find realistic estimates for conformational transitions between individual states of the transport cycle. When constrained by experimental results, kinetic models can faithfully describe the function of a candidate transporter at a pre-steady state. In addition, we show that kinetic models can accurately predict the intra- and extracellular substrate concentrations maintained by the transporter at a steady state, even under the premise of loose coupling between the electrochemical gradient of the driving ion and of the substrate. We define the criteria for the design of a credible kinetic model of the SLC transporter. Parsimony is the guiding principle of kinetic modeling. We argue, however, that the level of acceptable parsimony is limited by the need to account for the substrate gradient established by a secondary active transporter, and for random order binding of co-substrates and substrate. Random order binding has consistently been observed in transporters of the SLC group. Full article

(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)

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16 pages, 2628 KiB

Open AccessArticle

Structural Insights into AQP2 Targeting to Multivesicular Bodies

by Jennifer Virginia Roche, Veronika Nesverova, Caroline Olsson, Peter MT Deen and Susanna Törnroth-Horsefield

Int. J. Mol. Sci. 2019, 20(21), 5351; https://doi.org/10.3390/ijms20215351 - 28 Oct 2019

Cited by 11 | Viewed by 3368

Abstract

Vasopressin-dependent trafficking of AQP2 in the renal collecting duct is crucial for the regulation of water homeostasis. This process involves the targeting of AQP2 to the apical membrane during dehydration as well as its removal when hydration levels have been restored. The latter [...] Read more.

Vasopressin-dependent trafficking of AQP2 in the renal collecting duct is crucial for the regulation of water homeostasis. This process involves the targeting of AQP2 to the apical membrane during dehydration as well as its removal when hydration levels have been restored. The latter involves AQP2 endocytosis and sorting into multivesicular bodies (MVB), from where it may be recycled, degraded in lysosomes, or released into urine via exosomes. The lysosomal trafficking regulator-interacting protein 5 (LIP5) plays a crucial role in this by coordinating the actions of the endosomal sorting complex required for transport III (ESCRT-III) and vacuolar protein sorting 4 (Vps4) ATPase, resulting in the insertion of AQP2 into MVB inner vesicles. While the interaction between LIP5 and the ESCRT-III complex and Vps4 is well characterized, very little is known about how LIP5 interacts with AQP2 or any other membrane protein cargo. Here, we use a combination of fluorescence spectroscopy and computer modeling to provide a structural model of how LIP5 interacts with human AQP2. We demonstrate that, the AQP2 tetramer binds up to two LIP5 molecules and that the interaction is similar to that seen in the complex between LIP5 and the ESCRT-III component, charged multivesicular body protein 1B (CHMP1B). These studies give the very first structural insights into how LIP5 enables membrane protein insertion into MVB inner vesicles and significantly increase our understanding of the AQP2 trafficking mechanism. Full article

(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)

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12 pages, 6748 KiB

Open AccessArticle

Protein Abundance of Clinically Relevant Drug Transporters in The Human Kidneys

by Stefan Oswald, Janett Müller, Ute Neugebauer, Rita Schröter, Edwin Herrmann, Hermann Pavenstädt and Giuliano Ciarimboli

Int. J. Mol. Sci. 2019, 20(21), 5303; https://doi.org/10.3390/ijms20215303 - 24 Oct 2019

Cited by 33 | Viewed by 3878

Abstract

Renal drug transporters such as the organic cation transporters (OCTs), organic anion transporters (OATs) and multidrug resistance proteins (MRPs) play an important role in the tubular secretion of many drugs influencing their efficacy and safety. However, only little is known about the distinct [...] Read more.

Renal drug transporters such as the organic cation transporters (OCTs), organic anion transporters (OATs) and multidrug resistance proteins (MRPs) play an important role in the tubular secretion of many drugs influencing their efficacy and safety. However, only little is known about the distinct protein abundance of these transporters in human kidneys, and about the impact of age and gender as potential factors of inter-subject variability in their expression and function. The aim of this study was to determine the protein abundance of MDR1, MRP1-4, BCRP, OAT1-3, OCT2-3, MATE1, PEPT1/2, and ORCTL2 by liquid chromatography-tandem mass spectrometry-based targeted proteomics in a set of 36 human cortex kidney samples (20 males, 16 females; median age 53 and 55 years, respectively). OAT1 and 3, OCT2 and ORCTL2 were found to be most abundant renal SLC transporters while MDR1, MRP1 and MRP4 were the dominating ABC transporters. Only the expression levels of MDR1 and ORCTL2 were significantly higher abundant in older donors. Moreover, we found several significant correlations between different transporters, which may indicate their functional interplay in renal vectorial transport processes. Our data may contribute to a better understanding of the molecular processes determining renal excretion of drugs. Full article

(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)

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15 pages, 1396 KiB

Open AccessArticle

Species-Specific Glucose-6-Phosphatase Activity in the Small Intestine—Studies in Three Different Mammalian Models

by Viola Varga, Zsófia Murányi, Anita Kurucz, Paola Marcolongo, Angelo Benedetti, Gábor Bánhegyi and Éva Margittai

Int. J. Mol. Sci. 2019, 20(20), 5039; https://doi.org/10.3390/ijms20205039 - 11 Oct 2019

Cited by 10 | Viewed by 4351

Abstract

Besides the liver, which has always been considered the major source of endogenous glucose production in all post-absorptive situations, kidneys and intestines can also produce glucose in blood, particularly during fasting and under protein feeding. However, observations gained in different experimental animals have [...] Read more.

Besides the liver, which has always been considered the major source of endogenous glucose production in all post-absorptive situations, kidneys and intestines can also produce glucose in blood, particularly during fasting and under protein feeding. However, observations gained in different experimental animals have given ambiguous results concerning the presence of the glucose-6-phosphatase system in the small intestine. The aim of this study was to better define the species-related differences of this putative gluconeogenic organ in glucose homeostasis. The components of the glucose-6-phosphatase system (i.e., glucose-6-phosphate transporter and glucose-6-phosphatase itself) were analyzed in homogenates or microsomal fractions prepared from the small intestine mucosae and liver of rats, guinea pigs, and humans. Protein and mRNA levels, as well as glucose-6-phosphatase activities, were detected. The results showed that the glucose-6-phosphatase system is poorly represented in the small intestine of rats; on the other hand, significant expressions of glucose-6-phosphate transporter and of the glucose-6-phosphatase were found in the small intestine of guinea pigs and homo sapiens. The activity of the recently described fructose-6-phosphate transporter–intraluminal hexose isomerase pathway was also present in intestinal microsomes from these two species. The results demonstrate that the gluconeogenic role of the small intestine is highly species-specific and presumably dependent on feeding behavior (e.g., fructose consumption) and the actual state of metabolism. Full article

(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)

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19 pages, 3366 KiB

Open AccessArticle

BMAL1 Disrupted Intrinsic Diurnal Oscillation in Rat Cerebrovascular Contractility of Simulated Microgravity Rats by Altering Circadian Regulation of miR-103/Ca_V1.2 Signal Pathway

by Li Chen, Bin Zhang, Lu Yang, Yun-Gang Bai, Ji-Bo Song, Yi-Ling Ge, Hong-Zhe Ma, Jiu-Hua Cheng, Jin Ma and Man-Jiang Xie

Int. J. Mol. Sci. 2019, 20(16), 3947; https://doi.org/10.3390/ijms20163947 - 14 Aug 2019

Cited by 17 | Viewed by 3740

Abstract

The functional and structural adaptations in cerebral arteries could be one of the fundamental causes in the occurrence of orthostatic intolerance after space flight. In addition, emerging studies have found that many cardiovascular functions exhibit circadian rhythm. Several lines of evidence suggest that [...] Read more.

The functional and structural adaptations in cerebral arteries could be one of the fundamental causes in the occurrence of orthostatic intolerance after space flight. In addition, emerging studies have found that many cardiovascular functions exhibit circadian rhythm. Several lines of evidence suggest that space flight might increase an astronaut’s cardiovascular risks by disrupting circadian rhythm. However, it remains unknown whether microgravity disrupts the diurnal variation in vascular contractility and whether microgravity impacts on circadian clock system. Sprague-Dawley rats were subjected to 28-day hindlimb-unweighting to simulate the effects of microgravity on vasculature. Cerebrovascular contractility was estimated by investigating vasoconstrictor responsiveness and myogenic tone. The circadian regulation of Ca_V1.2 channel was determined by recording whole-cell currents, evaluating protein and mRNA expressions. Then the candidate miRNA in relation with Ca²⁺ signal was screened. Lastly, the underlying pathway involved in circadian regulation of cerebrovascular contractility was determined. The major findings of this study are: (1) The clock gene BMAL1 could induce the expression of miR-103, and in turn modulate the circadian regulation of Ca_V1.2 channel in rat cerebral arteries at post-transcriptional level; and (2) simulated microgravity disrupted intrinsic diurnal oscillation in rat cerebrovascular contractility by altering circadian regulation of BMAL1/miR-103/Ca_V1.2 signal pathway. Full article

(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)

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13 pages, 2400 KiB

Open AccessArticle

Different Actions of Intracellular Zinc Transporters ZIP7 and ZIP13 Are Essential for Dermal Development

by Mi-Gi Lee and Bum-Ho Bin

Int. J. Mol. Sci. 2019, 20(16), 3941; https://doi.org/10.3390/ijms20163941 - 13 Aug 2019

Cited by 15 | Viewed by 3641

Abstract

Two mesenchymal zinc transporters, ZIP7 and ZIP13, play critical roles in dermal development. ZIP7 and ZIP13 are the closest among the conserved mammalian zinc transporters. However, whether their functions are complementary remains a controversial issue. In the present study, we found that the [...] Read more.

Two mesenchymal zinc transporters, ZIP7 and ZIP13, play critical roles in dermal development. ZIP7 and ZIP13 are the closest among the conserved mammalian zinc transporters. However, whether their functions are complementary remains a controversial issue. In the present study, we found that the expression of ZIP13, but not ZIP7, is elevated by transforming growth factor beta (TGF-β) treatment, indicating that TGF-β-mediated ZIP13 amplification is crucial for collagen production during dermal development. Genome-wide gene expression analysis revealed that ~26% of genes are dependent on either ZIP7 or ZIP13, which is greater than the ~17% of genes dependent on both of them. ZIP7 depletion induces endoplasmic reticulum (ER) stress in mesenchymal stem cells, resulting in significant inhibition of fibrogenic differentiation. However, ZIP13 depletion does not induce ER stress. Though both ZIP7 and ZIP13 contain traditional ER signal peptides for their intracellular localization, their distributions are distinct. When ZIP7 and ZIP13 are coexpressed, their localizations are distinct; ZIP7 is located on the ER, but ZIP13 is located on both the ER and Golgi, indicating that only ZIP13 is a zinc gatekeeper on the Golgi. Our data illustrate that the different actions of ZIP7 and ZIP13 are crucial for dermal development. Full article

(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)

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Review

Jump to: Research

18 pages, 2406 KiB

Open AccessReview

The Fundamental Role of Bicarbonate Transporters and Associated Carbonic Anhydrase Enzymes in Maintaining Ion and pH Homeostasis in Non-Secretory Organs

by Dongun Lee and Jeong Hee Hong

Int. J. Mol. Sci. 2020, 21(1), 339; https://doi.org/10.3390/ijms21010339 - 4 Jan 2020

Cited by 34 | Viewed by 9363

Abstract

The bicarbonate ion has a fundamental role in vital systems. Impaired bicarbonate transport leads to various diseases, including immune disorders, cystic fibrosis, tumorigenesis, kidney diseases, brain dysfunction, tooth fracture, ischemic reperfusion injury, hypertension, impaired reproductive system, and systemic acidosis. Carbonic anhydrases are involved [...] Read more.

The bicarbonate ion has a fundamental role in vital systems. Impaired bicarbonate transport leads to various diseases, including immune disorders, cystic fibrosis, tumorigenesis, kidney diseases, brain dysfunction, tooth fracture, ischemic reperfusion injury, hypertension, impaired reproductive system, and systemic acidosis. Carbonic anhydrases are involved in the mechanism of bicarbonate movement and consist of complex of bicarbonate transport systems including bicarbonate transporters. This review focused on the convergent regulation of ion homeostasis through various ion transporters including bicarbonate transporters, their regulatory enzymes, such as carbonic anhydrases, pH regulatory role, and the expression pattern of ion transporters in non-secretory systems throughout the body. Understanding the correlation between these systems will be helpful in order to obtain new insights and design potential therapeutic strategies for the treatment of pH-related disorders. In this review, we have discussed the broad prospects and challenges that remain in elucidation of bicarbonate-transport-related biological and developmental systems. Full article

(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)

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24 pages, 1168 KiB

Open AccessReview

Glucose Transport and Transporters in the Endomembranes

by Beáta Lizák, András Szarka, Yejin Kim, Kyu-sung Choi, Csilla E. Németh, Paola Marcolongo, Angelo Benedetti, Gábor Bánhegyi and Éva Margittai

Int. J. Mol. Sci. 2019, 20(23), 5898; https://doi.org/10.3390/ijms20235898 - 24 Nov 2019

Cited by 53 | Viewed by 15108

Abstract

Glucose is a basic nutrient in most of the creatures; its transport through biological membranes is an absolute requirement of life. This role is fulfilled by glucose transporters, mediating the transport of glucose by facilitated diffusion or by secondary active transport. GLUT (glucose [...] Read more.

Glucose is a basic nutrient in most of the creatures; its transport through biological membranes is an absolute requirement of life. This role is fulfilled by glucose transporters, mediating the transport of glucose by facilitated diffusion or by secondary active transport. GLUT (glucose transporter) or SLC2A (Solute carrier 2A) families represent the main glucose transporters in mammalian cells, originally described as plasma membrane transporters. Glucose transport through intracellular membranes has not been elucidated yet; however, glucose is formed in the lumen of various organelles. The glucose-6-phosphatase system catalyzing the last common step of gluconeogenesis and glycogenolysis generates glucose within the lumen of the endoplasmic reticulum. Posttranslational processing of the oligosaccharide moiety of glycoproteins also results in intraluminal glucose formation in the endoplasmic reticulum (ER) and Golgi. Autophagic degradation of polysaccharides, glycoproteins, and glycolipids leads to glucose accumulation in lysosomes. Despite the obvious necessity, the mechanism of glucose transport and the molecular nature of mediating proteins in the endomembranes have been hardly elucidated for the last few years. However, recent studies revealed the intracellular localization and functional features of some glucose transporters; the aim of the present paper was to summarize the collected knowledge. Full article

(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)

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17 pages, 852 KiB

Open AccessReview

The Pivotal Role of TRP Channels in Homeostasis and Diseases throughout the Gastrointestinal Tract

by Alessandro Alaimo and Josep Rubert

Int. J. Mol. Sci. 2019, 20(21), 5277; https://doi.org/10.3390/ijms20215277 - 24 Oct 2019

Cited by 22 | Viewed by 4949

Abstract

The transient receptor potential (TRP) channels superfamily are a large group of proteins that play crucial roles in cellular processes. For example, these cation channels act as sensors in the detection and transduction of stimuli of temperature, small molecules, voltage, pH, and mechanical [...] Read more.

The transient receptor potential (TRP) channels superfamily are a large group of proteins that play crucial roles in cellular processes. For example, these cation channels act as sensors in the detection and transduction of stimuli of temperature, small molecules, voltage, pH, and mechanical constrains. Over the past decades, different members of the TRP channels have been identified in the human gastrointestinal (GI) tract playing multiple modulatory roles. Noteworthy, TRPs support critical functions related to the taste perception, mechanosensation, and pain. They also participate in the modulation of motility and secretions of the human gut. Last but not least, altered expression or activity and mutations in the TRP genes are often related to a wide range of disorders of the gut epithelium, including inflammatory bowel disease, fibrosis, visceral hyperalgesia, irritable bowel syndrome, and colorectal cancer. TRP channels could therefore be promising drug targets for the treatment of GI malignancies. This review aims at providing a comprehensive picture of the most recent advances highlighting the expression and function of TRP channels in the GI tract, and secondly, the description of the potential roles of TRPs in relevant disorders is discussed reporting our standpoint on GI tract–TRP channels interactions. Full article

(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)

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14 pages, 333 KiB

Open AccessReview

Aquaporins Involvement in Pancreas Physiology and in Pancreatic Diseases

by Tatjana Arsenijevic, Jason Perret, Jean-Luc Van Laethem and Christine Delporte

Int. J. Mol. Sci. 2019, 20(20), 5052; https://doi.org/10.3390/ijms20205052 - 11 Oct 2019

Cited by 23 | Viewed by 4428

Abstract

Aquaporins are a family of transmembrane proteins permeable to water. In mammals, they are subdivided into classical aquaporins that are permeable to water; aquaglyceroporins that are permeable to water, glycerol and urea; peroxiporins that facilitate the diffusion of H₂O₂ through [...] Read more.

Aquaporins are a family of transmembrane proteins permeable to water. In mammals, they are subdivided into classical aquaporins that are permeable to water; aquaglyceroporins that are permeable to water, glycerol and urea; peroxiporins that facilitate the diffusion of H₂O₂ through cell membranes; and so called unorthodox aquaporins. Aquaporins ensure important physiological functions in both exocrine and endocrine pancreas. Indeed, they are involved in pancreatic fluid secretion and insulin secretion. Modification of aquaporin expression and/or subcellular localization may be involved in the pathogenesis of pancreatic insufficiencies, diabetes and pancreatic cancer. Aquaporins may represent useful drug targets for the treatment of pathophysiological conditions affecting pancreatic function, and/or diagnostic/predictive biomarker for pancreatic cancer. This review summarizes the current knowledge related to the involvement of aquaporins in the pancreas physiology and physiopathology. Full article

(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)

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Channels and Transporters in Cells and Tissues

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