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Molecular Mechanism of pH Regulation: From Physiology to Pathology

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 20060

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Dr. Inyeong Choi

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Guest Editor

Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA
Interests: pH regulation; acid/base disturbance; metabolic acidosis; sodium-bicarbonate transporter; brain acidosis; acidosis in cancer; structure-function of acid/base transporter
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Dear Colleagues,

The pH in extracellular fluid is normally maintained at 7.4, equivalent to one H+ ion per 25 million water molecules. Despite such extremely low levels, H+ has profound effects on function, as it binds to proteins and alters their structure and properties. A variety of proteins, including receptors, signal transduction molecules, enzymes, and structural proteins, can be altered in their function by H+, thereby interfering with their cellular and systemic roles. Maintaining normal pH is frequently challenged by both physiological and pathological conditions. For example, acidification occurs as metabolic activity increases (such as during heavy exercise) or when blood supply is inefficient in disease states (such as ischemia and cancer). Numerous proteins are inhibited by high H+ levels, and thus, acidification inhibits cellular activity. Severe acidification is deleterious to normal cells, causing cell death. However, acidification can be adversely beneficial under some pathological conditions. Cancer cells thrive in an acidic environment and undergo adaptations to promote survival and proliferation, such that acidic pH stimulates cancer cell growth, migration, and invasion. The effects of pH abnormalities on physiological functions and relevant diseases have been extensively studied for the past decades. Despite considerable progress, though, the fundamental question of how pH is regulated at the molecular level is unclear. The current Special Issue focuses on progress toward understanding the molecular mechanism of pH regulation under physiological conditions and its involvement in pathogenesis. The topic is open to original studies, reviews, and new methodologies, ranging from molecular and cellular level to integrated organ systems.

Dr. Inyeong Choi
Guest Editor

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Keywords

pH regulation
acid base transporter
acid base disturbance
acidosis
intracellular pH
NBC
NHE
cancer

Published Papers (6 papers)

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Research

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12 pages, 2061 KiB

Open AccessArticle

In Vivo Functional Assay in Fish Gills: Exploring Branchial Acid-Excreting Mechanisms in Zebrafish

by Shang-Wu Shih, Jia-Jiun Yan, Yi-Ling Tsou, Shao-Wei Lu, Min-Chen Wang, Ming-Yi Chou and Pung-Pung Hwang

Int. J. Mol. Sci. 2022, 23(8), 4419; https://doi.org/10.3390/ijms23084419 - 16 Apr 2022

Cited by 5 | Viewed by 1803

Abstract

Molecular and physiological analyses in ionoregulatory organs (e.g., adult gills and embryonic skin) are essential for studying fish ion regulation. Recent progress in the molecular physiology of fish ion regulation was mostly obtained in embryonic skin; however, studies of ion regulation in adult gills are still elusive and limited because there are no direct methods for in vivo functional assays in the gills. The present study applied the scanning ion-selective electrode technique (SIET) in adult gills to investigate branchial H⁺-excreting functions in vivo. We removed the opercula from zebrafish and then performed long-term acid acclimation experiments. The results of Western blot and immunofluorescence showed that the protein expression of H⁺-ATPase (HA) and the number of H⁺-ATPase-rich ionocytes were increased under acidic situations. The SIET results proved that the H⁺ excretion capacity is indeed enhanced in the gills acclimated to acidic water. In addition, both HA and Na⁺/H⁺ exchanger (Nhe) inhibitors suppressed the branchial H⁺ excretion capacity, suggesting that H⁺ is excreted in association with HA and Nhe in zebrafish gills. These results demonstrate that SIET is effective for in vivo detection in fish gills, representing a breakthrough approach for studying the molecular physiology of fish ion regulation. Full article

(This article belongs to the Special Issue Molecular Mechanism of pH Regulation: From Physiology to Pathology)

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20 pages, 82833 KiB

Open AccessArticle

pH-Sensing G Protein-Coupled Receptor OGR1 (GPR68) Expression and Activation Increases in Intestinal Inflammation and Fibrosis

by Cheryl de Vallière, Jesus Cosin-Roger, Katharina Baebler, Anja Schoepflin, Céline Mamie, Michelle Mollet, Cordelia Schuler, Susan Bengs, Silvia Lang, Michael Scharl, Klaus Seuwen, Pedro A. Ruiz, Martin Hausmann and Gerhard Rogler

Int. J. Mol. Sci. 2022, 23(3), 1419; https://doi.org/10.3390/ijms23031419 - 26 Jan 2022

Cited by 9 | Viewed by 3965

Abstract

Local extracellular acidification occurs at sites of inflammation. Proton-sensing ovarian cancer G-protein-coupled receptor 1 (OGR1, also known as GPR68) responds to decreases in extracellular pH. Our previous studies show a role for OGR1 in the pathogenesis of mucosal inflammation, suggesting a link between tissue pH and immune responses. Additionally, pH-dependent signalling is associated with the progression of intestinal fibrosis. In this study, we aimed to investigate OGR1 expression and OGR1-mediated signalling in patients with inflammatory bowel disease (IBD). Our results show that OGR1 expression significantly increased in patients with IBD compared to non-IBD patients, as demonstrated by qPCR and immunohistochemistry (IHC). Paired samples from non-inflamed and inflamed intestinal areas of IBD patients showed stronger OGR1 IHC staining in inflamed mucosal segments compared to non-inflamed mucosa. IHC of human surgical samples revealed OGR1 expression in macrophages, granulocytes, endothelial cells, and fibroblasts. OGR1-dependent inositol phosphate (IP) production was significantly increased in CD14+ monocytes from IBD patients compared to healthy subjects. Primary human and murine fibroblasts exhibited OGR1-dependent IP formation, RhoA activation, F-actin, and stress fibre formation upon an acidic pH shift. OGR1 expression and signalling increases with IBD disease activity, suggesting an active role of OGR1 in the pathogenesis of IBD. Full article

(This article belongs to the Special Issue Molecular Mechanism of pH Regulation: From Physiology to Pathology)

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14 pages, 1591 KiB

Open AccessArticle

Lack of Charge Interaction in the Ion Binding Site Determines Anion Selectivity in the Sodium Bicarbonate Cotransporter NBCe1

by Soojung Lee, Jason Lin and Inyeong Choi

Int. J. Mol. Sci. 2022, 23(1), 532; https://doi.org/10.3390/ijms23010532 - 4 Jan 2022

Viewed by 1369

Abstract

The Na/HCO₃ cotransporter NBCe1 is a member of SLC4A transporters that move HCO₃⁻ across cell membranes and regulate intracellular pH or transepithelial HCO₃ transport. NBCe1 is highly selective to HCO₃⁻ and does not transport other anions; the molecular mechanism of anion selectivity is presently unclear. We previously reported that replacing Asp⁵⁵⁵ with a Glu (D555E) in NBCe1 induces increased selectivity to other anions, including Cl⁻. This finding is unexpected because all SLC4A transporters contain either Asp or Glu at the corresponding position and maintain a high selectivity to HCO₃⁻. In this study, we tested whether the Cl⁻ transport in D555E is mediated by an interaction between residues in the ion binding site. Human NBCe1 and mutant transporters were expressed in Xenopus oocytes, and their ability to transport Cl⁻ was assessed by two-electrode voltage clamp. The results show that the Cl⁻ transport is induced by a charge interaction between Glu⁵⁵⁵ and Lys⁵⁵⁸. The bond length between the two residues is within the distance for a salt bridge, and the ionic strength experiments confirm an interaction. This finding indicates that the HCO₃⁻ selectivity in NBCe1 is established by avoiding a specific charge interaction in the ion binding site, rather than maintaining such an interaction. Full article

(This article belongs to the Special Issue Molecular Mechanism of pH Regulation: From Physiology to Pathology)

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17 pages, 1750 KiB

Open AccessArticle

Revisiting the Role of Ser982 Phosphorylation in Stoichiometry Shift of the Electrogenic Na⁺/qHCO₃⁻ Cotransporter NBCe1

by Thamer A. Alsufayan, Evan J. Myers, Bianca N. Quade, Clayton T. Brady, Aniko Marshall, Nayem Haque, Michael E. Duffey and Mark D. Parker

Int. J. Mol. Sci. 2021, 22(23), 12817; https://doi.org/10.3390/ijms222312817 - 26 Nov 2021

Cited by 1 | Viewed by 2321

Abstract

In most cell types and heterologous expression systems, the electrogenic sodium-bicarbonate cotransporter NBCe1 operates with a 1Na⁺–2HCO₃⁻ stoichiometry that, given typical transmembrane electrochemical gradients, promotes Na+ and HCO₃⁻ influx. However, NBCe1 in the kidney mediates HCO₃⁻ efflux (HCO₃⁻ reabsorption), a direction that has been predicted to be favored only if NBCe1 operates with a 1:3 stoichiometry. The phosphorylation state of Ser982 in the cytosolic carboxy-terminal domain of NBCe1 has been reported to be a key determinant of the transporter stoichiometry, with non-phosphorylated Ser982 favoring a 1:3 stoichiometry. Conversely, phosphoproteomic data from renal cortical preparations have revealed the presence of NBCe1 peptides including phosphoserine982 (pSer982) and/or pSer985 although it was not known what proportion of NBCe1 molecules were phosphorylated. In the present study, we report the generation, characterization, and application of a novel phosphospecific antibody raised against NBCe1/pSer982 and show that, contrary to expectations, Ser982 is more prevalently phosphorylated in murine kidneys (in which NBCe1 mediates HCO₃⁻ efflux) than in murine colons (in which NBCe1 mediates HCO₃⁻ influx). Using phosphomimetic mutants of murine NBCe1 expressed in Xenopus oocytes, we found no evidence that the phosphorylation state of Ser982 or Ser985 alone influences the transport stoichiometry or conductance. Furthermore, we found that the phosphorylation of NBCe1/Ser982 is enhanced in murine kidneys following a 24 h induction of metabolic acidosis. We conclude that the phosphorylation status of Ser982 is not a key determinant of NBCe1 stoichiometry but correlates with presumed NBCe1 activity. Full article

(This article belongs to the Special Issue Molecular Mechanism of pH Regulation: From Physiology to Pathology)

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Review

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17 pages, 574 KiB

Open AccessReview

Regulation of Cytosolic pH: The Contributions of Plant Plasma Membrane H⁺-ATPases and Multiple Transporters

by Jin-Yan Zhou, Dong-Li Hao and Guang-Zhe Yang

Int. J. Mol. Sci. 2021, 22(23), 12998; https://doi.org/10.3390/ijms222312998 - 30 Nov 2021

Cited by 20 | Viewed by 3355

Abstract

Cytosolic pH homeostasis is a precondition for the normal growth and stress responses in plants, and H⁺ flux across the plasma membrane is essential for cytoplasmic pH control. Hence, this review focuses on seven types of proteins that possess direct H⁺ transport activity, namely, H⁺-ATPase, NHX, CHX, AMT, NRT, PHT, and KT/HAK/KUP, to summarize their plasma-membrane-located family members, the effect of corresponding gene knockout and/or overexpression on cytosolic pH, the H⁺ transport pathway, and their functional regulation by the extracellular/cytosolic pH. In general, H⁺-ATPases mediate H⁺ extrusion, whereas most members of other six proteins mediate H⁺ influx, thus contributing to cytosolic pH homeostasis by directly modulating H⁺ flux across the plasma membrane. The fact that some AMTs/NRTs mediate H⁺-coupled substrate influx, whereas other intra-family members facilitate H⁺-uncoupled substrate transport, demonstrates that not all plasma membrane transporters possess H⁺-coupled substrate transport mechanisms, and using the transport mechanism of a protein to represent the case of the entire family is not suitable. The transport activity of these proteins is regulated by extracellular and/or cytosolic pH, with different structural bases for H⁺ transfer among these seven types of proteins. Notably, intra-family members possess distinct pH regulatory characterization and underlying residues for H⁺ transfer. This review is anticipated to facilitate the understanding of the molecular basis for cytosolic pH homeostasis. Despite this progress, the strategy of their cooperation for cytosolic pH homeostasis needs further investigation. Full article

(This article belongs to the Special Issue Molecular Mechanism of pH Regulation: From Physiology to Pathology)

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17 pages, 751 KiB

Open AccessReview

Decreased Brain pH and Pathophysiology in Schizophrenia

by Hae-Jeong Park, Inyeong Choi and Kang-Hyun Leem

Int. J. Mol. Sci. 2021, 22(16), 8358; https://doi.org/10.3390/ijms22168358 - 4 Aug 2021

Cited by 22 | Viewed by 6388

Abstract

Postmortem studies reveal that the brain pH in schizophrenia patients is lower than normal. The exact cause of this low pH is unclear, but increased lactate levels due to abnormal energy metabolism appear to be involved. Schizophrenia patients display distinct changes in mitochondria number, morphology, and function, and such changes promote anaerobic glycolysis, elevating lactate levels. pH can affect neuronal activity as H⁺ binds to numerous proteins in the nervous system and alters the structure and function of the bound proteins. There is growing evidence of pH change associated with cognition, emotion, and psychotic behaviors. Brain has delicate pH regulatory mechanisms to maintain normal pH in neurons/glia and extracellular fluid, and a change in these mechanisms can affect, or be affected by, neuronal activities associated with schizophrenia. In this review, we discuss the current understanding of the cause and effect of decreased brain pH in schizophrenia based on postmortem human brains, animal models, and cellular studies. The topic includes the factors causing decreased brain pH in schizophrenia, mitochondria dysfunction leading to altered energy metabolism, and pH effects on the pathophysiology of schizophrenia. We also review the acid/base transporters regulating pH in the nervous system and discuss the potential contribution of the major transporters, sodium hydrogen exchangers (NHEs), and sodium-coupled bicarbonate transporters (NCBTs), to schizophrenia. Full article

(This article belongs to the Special Issue Molecular Mechanism of pH Regulation: From Physiology to Pathology)

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