scholarly journals Tonic inhibition of the chloride/proton antiporter ClC-7 by PI(3,5)P2 is crucial for lysosomal pH maintenance

2021 ◽  
Author(s):  
Joseph A Mindell ◽  
Xavier Leray ◽  
Jacob K Hilton ◽  
Kamsi Nwangwu ◽  
Alissa Becerril ◽  
...  
Keyword(s):  
Ion Channels ◽  
Narrow Range ◽  
Ph Regulation ◽  
Tonic Inhibition ◽  
Gain Of Function ◽  
Lysosomal Ph ◽  
Ion Movement ◽  
Luminal Ph

The acidic luminal pH of lysosomes, maintained within a narrow range, is essential for proper degrative function of the organelle and is generated by the action of a V-type H+ ATPase, but other pathways for ion movement are required to dissipate the voltage generated by this process. ClC-7, a Cl-/H+ antiporter responsible for lysosomal Cl- permeability, is a candidate to contribute to the acidification process as part of this “counterion pathway”. The signaling lipid PI(3,5)P2 modulates lysosomal dynamics, including by regulating lysosomal ion channels, raising the possibility that it could contribute to lysosomal pH regulation. Here we demonstrate that depleting PI(3,5)P2 by inhibiting the PIKfyve kinase causes lysosomal hyperacidification, primarily via an effect on ClC-7. We further show that PI(3,5)P2 directly inhibits ClC-7 transport and that this inhibition is eliminated in a disease-causing gain-of-function ClC-7 mutation. Together these observations suggest an intimate role for ClC-7 in lysosomal pH regulation.

scholarly journals A model of lysosomal pH regulation

2013 ◽  
Vol 141 (6) ◽  
pp. 705-720 ◽  
Author(s):  
Yoichi Ishida ◽  
Smita Nayak ◽  
Joseph A. Mindell ◽  
Michael Grabe
Keyword(s):  
Ph Regulation ◽  
Hydrolytic Enzymes ◽  
Na Channels ◽  
Lysosomal Ph ◽  
Current Voltage ◽  
Current Voltage Characteristics ◽  
Luminal Ph ◽  
Rule Out

Lysosomes must maintain an acidic luminal pH to activate hydrolytic enzymes and degrade internalized macromolecules. Acidification requires the vacuolar-type H+-ATPase to pump protons into the lumen and a counterion flux to neutralize the membrane potential created by proton accumulation. Early experiments suggested that the counterion was chloride, and more recently a pathway consistent with the ClC-7 Cl–/H+ antiporter was identified. However, reports that the steady-state luminal pH is unaffected in ClC-7 knockout mice raise questions regarding the identity of the carrier and the counterion. Here, we measure the current–voltage characteristics of a mammalian ClC-7 antiporter, and we use its transport properties, together with other key ion regulating elements, to construct a mathematical model of lysosomal pH regulation. We show that results of in vitro lysosome experiments can only be explained by the presence of ClC-7, and that ClC-7 promotes greater acidification than Cl–, K+, or Na+ channels. Our models predict strikingly different lysosomal K+ dynamics depending on the major counterion pathways. However, given the lack of experimental data concerning acidification in vivo, the model cannot definitively rule out any given mechanism, but the model does provide concrete predictions for additional experiments that would clarify the identity of the counterion and its carrier.

scholarly journals Extracellular and Luminal pH Regulation by Vacuolar H+-ATPase Isoform Expression and Targeting to the Plasma Membrane and Endosomes

2016 ◽  
Vol 291 (16) ◽  
pp. 8500-8515 ◽  
Author(s):  
Gina A. Smith ◽  
Gareth J. Howell ◽  
Clair Phillips ◽  
Stephen P. Muench ◽  
Sreenivasan Ponnambalam ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Ph Regulation ◽  
Luminal Ph ◽  
Isoform Expression

scholarly journals Gain-of-Function Mutations in the Transient Receptor Potential Channels TRPV1 and TRPA1: How Painful?

2014 ◽  
pp. S205-S213 ◽  
Author(s):  
S. BOUKALOVA ◽  
F. TOUSKA ◽  
L. MARSAKOVA ◽  
A. HYNKOVA ◽  
L. SURA ◽  
...  
Keyword(s):  
Ion Channels ◽  
Transient Receptor Potential ◽  
Pain Syndrome ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Single Amino Acid ◽  
Voltage Sensitivity ◽  
Gain Of Function ◽  
Potential Channels ◽  
Transient Receptor

Gain-of-function (GOF) mutations in ion channels are rare events, which lead to increased agonist sensitivity or altered gating properties, and may render the channel constitutively active. Uncovering and following characterization of such mutants contribute substantially to the understanding of the molecular basis of ion channel functioning. Here we give an overview of some GOF mutants in polymodal ion channels specifically involved in transduction of painful stimuli – TRPV1 and TRPA1, which are scrutinized by scientists due to their important role in development of some pathological pain states. Remarkably, a substitution of single amino acid in the S4-S5 region of TRPA1 (N855S) has been recently associated with familial episodic pain syndrome. This mutation increases chemical sensitivity of TRPA1, but leaves the voltage sensitivity unchanged. On the other hand, mutations in the analogous region of TRPV1 (R557K and G563S) severely affect all aspects of channel activation and lead to spontaneous activity. Comparison of the effects induced by mutations in homologous positions in different TRP receptors (or more generally in other distantly related ion channels) may elucidate the gating mechanisms conserved during evolution.

scholarly journals SARS-CoV-2 treatment effects induced by ACE2-expressing microparticles are explained by the oxidized cholesterol-increased endosomal pH of alveolar macrophages

2022 ◽  
Author(s):  
Zhenfeng Wang ◽  
Jiadi Lv ◽  
Pin Yu ◽  
Yajin Qu ◽  
Yabo Zhou ◽  
...  
Keyword(s):  
Alveolar Macrophages ◽  
Ph Regulation ◽  
Proton Pumps ◽  
Lysosomal Ph ◽  
Oxidized Cholesterol ◽  
Endosomal Acidification ◽  
Endosomal Membranes ◽  
Endosomal Ph ◽  
Advanced Biomaterials ◽  
Potential Use

AbstractExploring the cross-talk between the immune system and advanced biomaterials to treat SARS-CoV-2 infection is a promising strategy. Here, we show that ACE2-overexpressing A549 cell-derived microparticles (AO-MPs) are a potential therapeutic agent against SARS-CoV-2 infection. Intranasally administered AO-MPs dexterously navigate the anatomical and biological features of the lungs to enter the alveoli and are taken up by alveolar macrophages (AMs). Then, AO-MPs increase the endosomal pH but decrease the lysosomal pH in AMs, thus escorting bound SARS-CoV-2 from phago-endosomes to lysosomes for degradation. This pH regulation is attributable to oxidized cholesterol, which is enriched in AO-MPs and translocated to endosomal membranes, thus interfering with proton pumps and impairing endosomal acidification. In addition to promoting viral degradation, AO-MPs also inhibit the proinflammatory phenotype of AMs, leading to increased treatment efficacy in a SARS-CoV-2-infected mouse model without side effects. These findings highlight the potential use of AO-MPs to treat SARS-CoV-2-infected patients and showcase the feasibility of MP therapies for combatting emerging respiratory viruses in the future.

scholarly journals Erratum: Corrigendum: Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels

2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Juliette Albuisson ◽  
Swetha E. Murthy ◽  
Michael Bandell ◽  
Bertrand Coste ◽  
Hélène Louis-dit-Picard ◽  
...  
Keyword(s):  
Ion Channels ◽  
Gain Of Function

scholarly journals Intracellular pH Regulation and the Acid Delusion

2020 ◽  
Author(s):  
Sheldon Magder ◽  
Alexandr Magder ◽  
Gordan Samoukovic
Keyword(s):  
Chemical Analysis ◽  
Narrow Range ◽  
Ph Regulation ◽  
Intracellular Ph Regulation ◽  
The Third ◽  
Electrical Neutrality ◽  
Physical Chemical ◽  
Dependent Variables ◽  
Protein Functions ◽  
Independent Variable

The concentration H+ ([H+]) in intracellular fluid (ICF) must be maintained in a narrow range in all species for normal protein functions. Thus, mechanisms regulating ICF are of fundamental biological importance. Studies on the regulation of ICF [H+] have been hampered by use of pH notation,failure to consider the roles played by differences in the concentration of strong ions ( SID), the conservation of mass, the principle of electrical neutrality and that [H+] and [HCO3-] are dependent variables. This argument is based on the late Peter Stewart’s physical- chemical analysis of [H+] regulation reported in this journal nearly forty years ago. We start by outlining the principles of Stewart’s analysis and then provide a general understanding of its significance for regulation of ICF [H+]. The system may initially appear complex, but it becomes evident that changes in SID dominanate regulation of [H+]. The primary strong ions are Na+, K+ and Cl-, and a few organic strong anions. The second independent variable, PCO2, can easily be assessed. The third independent variable, the activity of intracellular weak acids ([Atot]), is much more complex but largely plays a modifying role. Attention to these principles potentially will provide new insights into ICF pH regulation.

scholarly journals Distinct roles for two Caenorhabditis elegans acid-sensing ion channels in an ultradian clock

2021 ◽  
Author(s):  
Eva Kaulich ◽  
Brian D Ackley ◽  
Yi Quan Tang ◽  
Iris Hardege ◽  
William Schafer ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Ion Channels ◽  
Ph Regulation ◽  
Basolateral Membrane ◽  
Motor Program ◽  
Biological Clocks ◽  
Sensing Properties ◽  
Metabolic Defects ◽  
Acid Sensing Ion Channels ◽  
Intracellular Ca

Biological clocks are fundamental to an organism′s health, controlling periodicity of behavior and metabolism. Here, we identify two acid-sensing ion channels, with very different proton sensing properties, and describe their role in an ultradian clock, the defecation motor program (DMP) of the nematode Caenorhabditis elegans. An ACD-5-containing channel, on the apical membrane of the intestinal epithelium, is essential for maintenance of luminal acidity, and thus the rhythmic oscillations in lumen pH. In contrast, the second channel, composed of FLR-1, ACD-3 and/or DEL-5, located on the basolateral membrane, controls the intracellular Ca2+ wave and forms a core component of the master oscillator that controls timing and rhythmicity of the DMP. flr-1 and acd-3/del-5 mutants show severe developmental and metabolic defects. We thus directly link the proton-sensing properties of these channels to their physiological roles in pH regulation and Ca2+ signaling, the generation of an ultradian oscillator, and its metabolic consequences.

scholarly journals Structural basis for ion selectivity in TMEM175 K+ channels

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Janine D Brunner ◽  
Roman P Jakob ◽  
Tobias Schulze ◽  
Yvonne Neldner ◽  
Anna Moroni ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Ph Regulation ◽  
Ion Selectivity ◽  
Selectivity Filter ◽  
Structural Basis ◽  
K Channels ◽  
X Ray ◽  
Lysosomal Ph ◽  
Additional Layer ◽  
Channel Opening

The TMEM175 family constitutes recently discovered K+channels that are important for autophagosome turnover and lysosomal pH regulation and are associated with the early onset of Parkinson Disease. TMEM175 channels lack a P-loop selectivity filter, a hallmark of all known K+ channels, raising the question how selectivity is achieved. Here, we report the X-ray structure of a closed bacterial TMEM175 channel in complex with a nanobody fusion-protein disclosing bound K+ ions. Our analysis revealed that a highly conserved layer of threonine residues in the pore conveys a basal K+ selectivity. An additional layer comprising two serines in human TMEM175 increases selectivity further and renders this channel sensitive to 4-aminopyridine and Zn2+. Our findings suggest that large hydrophobic side chains occlude the pore, forming a physical gate, and that channel opening by iris-like motions simultaneously relocates the gate and exposes the otherwise concealed selectivity filter to the pore lumen.

scholarly journals Acid-base regulation in the renal proximal tubules: using novel pH sensors to maintain homeostasis

2018 ◽  
Vol 315 (5) ◽  
pp. F1187-F1190 ◽  
Author(s):  
Premraj Rajkumar ◽  
Jennifer L. Pluznick
Keyword(s):  
Proximal Tubule ◽  
Narrow Range ◽  
Ph Regulation ◽  
Critical Role ◽  
Proximal Tubules ◽  
Ph Sensors ◽  
Ph Homeostasis ◽  
Acid Base ◽  
To Come

The kidneys play a critical role in precisely regulating the composition of the plasma to maintain homeostasis. To achieve this, the kidneys must be able to accurately determine or “sense” the concentration of a wide variety of substances and to make adjustments accordingly. Kidneys face a key challenge in the arena of pH balance, as there is a particularly narrow range over which plasma pH varies in a healthy subject (7.35–7.45) and this pH must constantly be protected against a variety of onslaughts (changes in diet, activity, and even elevation). The proximal tubule, the first segment to come into contact with the forming urine, plays an important role in helping the kidneys to maintain pH homeostasis. Recent studies have identified a number of novel proximal tubule proteins and signaling pathways that work to sense changes in pH and subsequently modulate renal pH regulation. In this review, we will highlight the role of novel players in acid-base homeostasis in the proximal tubule.

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