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The Journal of Physiological Sciences :... Nov 2023Physiological roles of Cl, a major anion in the body, are not well known compared with those of cations. This review article introduces: (1) roles of Cl in bodily and... (Review)
Review
Physiological roles of Cl, a major anion in the body, are not well known compared with those of cations. This review article introduces: (1) roles of Cl in bodily and cellular functions; (2) the range of cytosolic Cl concentration ([Cl]); (3) whether [Cl] could change with cell volume change under an isosmotic condition; (4) whether [Cl] could change under conditions where multiple Cl transporters and channels contribute to Cl influx and efflux in an isosmotic state; (5) whether the change in [Cl] could be large enough to act as signals; (6) effects of Cl on cytoskeletal tubulin polymerization through inhibition of GTPase activity and tubulin polymerization-dependent biological activity; (7) roles of cytosolic Cl in cell proliferation; (8) Cl-regulatory mechanisms of ciliary motility; (9) roles of Cl in sweet/umami taste receptors; (10) Cl-regulatory mechanisms of with-no-lysine kinase (WNK); (11) roles of Cl in regulation of epithelial Na transport; (12) relationship between roles of Cl and H in body functions.
Topics: Chlorides; Tubulin; Ion Transport; Biological Transport; Sodium; Chloride Channels
PubMed: 37968609
DOI: 10.1186/s12576-023-00889-x -
Frontiers in Bioscience (Landmark... Jan 2023The maintenance of intracellular and extracellular pH relies on multiple ion transporters/channels. Proton-activated chloride channel (PAC) precisely regulates... (Review)
Review
The maintenance of intracellular and extracellular pH relies on multiple ion transporters/channels. Proton-activated chloride channel (PAC) precisely regulates extracellular and early/late endosomal pH by transporting chloride ion (Cl-) across membranes and has been shown to be implicated in pH imbalance under hypoxic conditions, such as the acidic microenvironments of cancer and ischemia. In this article, the phenotypic characteristics, molecular mechanisms, physiology of PAC and its role in cancer, ischemic stroke and hypoxia will be discussed in order to provide some clues for developing potential therapeutic strategies.
Topics: Humans; Chloride Channels; Chlorides; Protons; Biological Transport; Hypoxia
PubMed: 36722267
DOI: 10.31083/j.fbl2801011 -
Indian Journal of Ophthalmology Apr 2023Dry eye disease (DED) which affects millions of people worldwide is an ocular surface disease that is strongly associated with pain, discomfort, and visual disturbances.... (Review)
Review
Dry eye disease (DED) which affects millions of people worldwide is an ocular surface disease that is strongly associated with pain, discomfort, and visual disturbances. Altered tear film dynamics, hyperosmolarity, ocular surface inflammation, and neurosensory abnormalities are the key contributors to DED pathogenesis. The presence of discordance between signs and symptoms of DED in patients and refractoriness to current therapies in some patients underpin the need for studying additional contributors that can be modulated. The presence of electrolytes or ions including sodium, potassium, chloride, bicarbonate, calcium, and magnesium in the tear fluid and ocular surface cells contribute to ocular surface homeostasis. Ionic or electrolyte imbalance and osmotic imbalance have been observed in DED and feed-forward interaction between ionic imbalances and inflammation alter cellular processes in the ocular surface resulting in DED. Ionic balances in various cellular and intercellular compartments are maintained by dynamic transport via ion channel proteins present in cell membranes. Hence, alterations in the expression and/or activity of about 33 types of ion channels that belong to voltage-gated channels, ligand-gated channels, mechanosensitive ion channel, aquaporins, chloride ion channel, sodium-potassium-chloride pumps or cotransporters have been investigated in the context of ocular surface health and DED in animal and/or human subjects. An increase in the expression or activity of TRPA1, TRPV1, Nav1.8, KCNJ6, ASIC1, ASIC3, P2X, P2Y, and NMDA receptor have been implicated in DED pathogenesis, whereas an increase in the expression or activity of TRPM8, GABA receptor, CFTR, and NKA have been associated with resolution of DED.
Topics: Animals; Humans; Chlorides; Dry Eye Syndromes; Eye; Tears; Vision Disorders; Inflammation
PubMed: 37026252
DOI: 10.4103/IJO.IJO_3020_22 -
The Journal of Biological Chemistry Jul 2019On the fiftieth anniversary of the discovery of the Ser-His-Asp catalytic triad, perhaps the most unusual variation on the textbook classic is described: An incomplete...
On the fiftieth anniversary of the discovery of the Ser-His-Asp catalytic triad, perhaps the most unusual variation on the textbook classic is described: An incomplete catalytic triad in a hydrolase is rescued by a chloride ion (Fig. 1). Structural and functional data provide compelling evidence that the active site of a phospholipase from employs the anion in place of the commonly observed Asp, reminding us that even well-trodden scientific ground has surprises in store.
Topics: Catalysis; Catalytic Domain; Chlorides; Hydrolases; Hydrolysis
PubMed: 31350284
DOI: 10.1074/jbc.H119.009687 -
Infection and Immunity Mar 2021Host colonization by a pathogen requires proper sensing and response to local environmental cues, to ensure adaptation and continued survival within the host. The ionic... (Review)
Review
Host colonization by a pathogen requires proper sensing and response to local environmental cues, to ensure adaptation and continued survival within the host. The ionic milieu represents a critical potential source of environmental cues, and indeed, there has been extensive study of the interplay between host and pathogen in the context of metals such as iron, zinc, and manganese, vital ions that are actively sequestered by the host. The inherent non-uniformity of the ionic milieu also extends, however, to "abundant" ions such as chloride and potassium, whose concentrations vary greatly between tissue and cellular locations, and with the immune response. Despite this, the concept of abundant ions as environmental cues and key players in host-pathogen interactions is only just emerging. Focusing on chloride and potassium, this review brings together studies across multiple bacterial and parasitic species that have begun to define both how these abundant ions are exploited as cues during host infection, and how they can be actively manipulated by pathogens during host colonization. The close links between ion homeostasis and sensing/response to different ionic signals, and the importance of studying pathogen response to cues in combination, are also discussed, while considering the fundamental insight still to be uncovered from further studies in this nascent area of inquiry.
Topics: Animals; Anions; Bacteria; Chlorides; Disease Susceptibility; Homeostasis; Host-Parasite Interactions; Host-Pathogen Interactions; Humans; Ions; Potassium
PubMed: 33526568
DOI: 10.1128/IAI.00641-20 -
Nutrients Mar 2024Potassium is a monovalent cation widely present in nature, where it is not in metallic form, but always in combination with other substances, especially chloride [...].
Potassium is a monovalent cation widely present in nature, where it is not in metallic form, but always in combination with other substances, especially chloride [...].
Topics: Humans; Potassium; Chlorides; Potassium Chloride
PubMed: 38542744
DOI: 10.3390/nu16060833 -
Pharmacological Reviews Oct 2019Endogenous ions play important roles in the function and pharmacology of G-protein coupled receptors (GPCRs). Historically the evidence for ionic modulation of GPCR... (Review)
Review
Endogenous ions play important roles in the function and pharmacology of G-protein coupled receptors (GPCRs). Historically the evidence for ionic modulation of GPCR function dates to 1973 with studies of opioid receptors, where it was demonstrated that physiologic concentrations of sodium allosterically attenuated agonist binding. This Na-selective effect was distinct from effects of other monovalent and divalent cations, with the latter usually counteracting sodium's negative allosteric modulation of binding. Since then, numerous studies documenting the effects of mono- and divalent ions on GPCR function have been published. While ions can act selectively and nonselectively at many sites in different receptors, the discovery of the conserved sodium ion site in class A GPCR structures in 2012 revealed the unique nature of Na site, which has emerged as a near-universal site for allosteric modulation of class A GPCR structure and function. In this review, we synthesize and highlight recent advances in the functional, biophysical, and structural characterization of ions bound to GPCRs. Taken together, these findings provide a molecular understanding of the unique roles of Na and other ions as GPCR allosteric modulators. We will also discuss how this knowledge can be applied to the redesign of receptors and ligand probes for desired functional and pharmacological profiles. SIGNIFICANCE STATEMENT: The function and pharmacology of GPCRs strongly depend on the presence of mono and divalent ions in experimental assays and in living organisms. Recent insights into the molecular mechanism of this ion-dependent allosterism from structural, biophysical, biochemical, and computational studies provide quantitative understandings of the pharmacological effects of drugs in vitro and in vivo and open new avenues for the rational design of chemical probes and drug candidates with improved properties.
Topics: Allosteric Site; Anions; Binding Sites; Cations, Divalent; Cations, Monovalent; Chlorides; Crystallography, X-Ray; Humans; Ligands; Protein Conformation; Receptors, G-Protein-Coupled; Sodium; Structure-Activity Relationship; Zinc
PubMed: 31551350
DOI: 10.1124/pr.119.017863 -
High sodium chloride affects BMP-7 and 1α-hydroxylase levels through NCC and CLC-5 in NRK-52E cells.Ecotoxicology and Environmental Safety Dec 2021A diet high in sodium chloride (NaCl) can affect renal function damage and increase urinary calcium excretion, leading to bone loss. in renal tubules, Na-Cl...
A diet high in sodium chloride (NaCl) can affect renal function damage and increase urinary calcium excretion, leading to bone loss. in renal tubules, Na-Cl co-transporter (NCC) and chloride channel 5 (CLC-5) are involved in regulating urinary calcium excretion. In addition, some cytokines, such as Bone morphogenetic protein 7 (BMP-7) and 1α-hydroxylase, are synthesized by renal tubules, which target on bone and play important roles on bone metabolism. However, the specific mechanisms between NaCl and these ion channels or cytokines still need investigations from many aspects. This study, in culture normal rat renal tubular epithelial NRK-52E cells, showed that high concentrations of NaCl significantly inhibited the cell viability and increased the cell apoptosis. High concentration of NaCl reduce bone mineral density (BMD), as demonstrated by the significantly increased mRNA and protein levels of NCC and osteopontin (OPN), but decreased the levels of CLC-5, BMP-7, and 1α-hydroxylase. In addition, we found that ovariectomized (OVX) rats on a high-salt diet for 12 weeks had altered levels of these indices in the renal cortices. Moreover, the BMD in fourth and fifth lumbar vertebra (LV4 and 5) and femurs were significantly decreased and bone microstructure was destroyed of these rats. We also demonstrated that high concentration of NaCl enhanced the inhibition of these cytokines which is beneficial to increase BMD, induced by modulating ion channels NCC and CLC-5. In conclusion, our results indicate that high concentration of NaCl reduce BMD by regulating ion channels NCC and CLC-5.
Topics: Animals; Bone Morphogenetic Protein 7; Chloride Channels; Chlorides; Mixed Function Oxygenases; Rats; Sodium Chloride
PubMed: 34530263
DOI: 10.1016/j.ecoenv.2021.112762 -
Experimental Physiology Mar 1997Until recently, the investigation of membrane ion transport mechanisms and their relationship with cataract formation has mainly focused on sodium, potassium and... (Review)
Review
Until recently, the investigation of membrane ion transport mechanisms and their relationship with cataract formation has mainly focused on sodium, potassium and calcium. The specific role of chloride in solute transport within the lens has been given little attention. Rather, chloride was considered as simply the counterion to sodium. The purpose of this review is to emphasize the importance of chloride and its involvement in the membrane ion transport systems within the lens. We summarize the general physiological and chemical properties of the chloride ion in the lens, with reference to the regional ion fluxes generated by its special anatomical and electrical structure. We also present our current knowledge of the principal ion transport mechanisms associated with chloride, with particular emphasis on Cl- channels, and discuss their possible physiological significance. Maintenance of a constant cell volume is an evolutionarily ancient homeostatic process and we present some important findings associated with volume regulatory mechanisms in the whole lens and in single lens cells. Finally, we review and discuss the link between cataract formation and chloride channel dysfunction.
Topics: Animals; Cataract; Chloride Channels; Chlorides; Humans; Lens, Crystalline
PubMed: 9129939
DOI: 10.1113/expphysiol.1997.sp004020 -
Philosophical Transactions of the Royal... Jan 2009The physiologically indispensable chloride channel (CLC) family is split into two classes of membrane proteins: chloride channels and chloride/proton antiporters. In... (Review)
Review
The physiologically indispensable chloride channel (CLC) family is split into two classes of membrane proteins: chloride channels and chloride/proton antiporters. In this article we focus on the relationship between these two groups and specifically review the role of protons in chloride-channel gating. Moreover, we discuss the evidence for proton transport through the chloride channels and explore the possible pathways that the protons could take through the chloride channels. We present results of a mutagenesis study, suggesting the feasibility of one of the pathways, which is closely related to the proton pathway proposed previously for the chloride/proton antiporters. We conclude that the two groups of CLC proteins, although in principle very different, employ similar mechanisms and pathways for ion transport.
Topics: Chloride Channels; Chlorides; Ion Channel Gating; Protons
PubMed: 18957380
DOI: 10.1098/rstb.2008.0123