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Biophysical Journal Mar 2011ClC-4 is a secondary active transporter that exchanges Cl(-) ions and H(+) with a 2:1 stoichiometry. In external SCN(-), ClC-4 becomes uncoupled and transports anions...
ClC-4 is a secondary active transporter that exchanges Cl(-) ions and H(+) with a 2:1 stoichiometry. In external SCN(-), ClC-4 becomes uncoupled and transports anions with high unitary transport rate. Upon voltage steps, the number of active transporters varies in a time-dependent manner, resembling voltage-dependent gating of ion channels. We here investigated modification of the voltage dependence of uncoupled ClC-4 by protons and anions to quantify association of substrates with the transporter. External acidification shifts voltage dependence of ClC-4 transport to more positive potentials and leads to reduced transport currents. Internal pH changes had less pronounced effects. Uncoupled ClC-4 transport is facilitated by elevated external [SCN(-)] but impaired by internal Cl(-) and I(-). Block by internal anions indicates the existence of an internal anion-binding site with high affinity that is not present in ClC channels. The voltage dependence of ClC-4 coupled transport is modulated by external protons and internal Cl(-) in a manner similar to what is observed under uncoupling conditions. Our data illustrate functional differences but also similarities between ClC channels and transporters.
Topics: Anions; Chloride Channels; Electricity; Extracellular Space; HEK293 Cells; Humans; Hydrogen-Ion Concentration; Intracellular Space; Ion Channel Gating; Protons
PubMed: 21354396
DOI: 10.1016/j.bpj.2011.01.045 -
Molecules (Basel, Switzerland) Dec 2020Lanthanide complexes have been developed and are reported herein. These complexes were derived from a terpyridine-functionalized calix[4]arene ligand, chelated with Tb...
Lanthanide complexes have been developed and are reported herein. These complexes were derived from a terpyridine-functionalized calix[4]arene ligand, chelated with Tb and Eu. Synthesis of these complexes was achieved in two steps from a calix[4]arene derivative: (1) amide coupling of a calix[4]arene bearing carboxylic acid functionalities and (2) metallation with a lanthanide triflate salt. The ligand and its complexes were characterized by NMR (H and C), fluorescence and UV-vis spectroscopy as well as MS. The photophysical properties of these complexes were studied; high molar absorptivity values, modest quantum yields and luminescence lifetimes on the ms timescale were obtained. Anion binding results in a change in the photophysical properties of the complexes. The anion sensing ability of the Tb(III) complex was evaluated via visual detection, UV-vis and fluorescence studies. The sensor was found to be responsive towards a variety of anions, and large binding constants were obtained for the coordination of anions to the sensor.
Topics: Anions; Biosensing Techniques; Calixarenes; Lanthanoid Series Elements; Ligands; Pyridines; Spectrometry, Fluorescence; Temperature
PubMed: 33375511
DOI: 10.3390/molecules26010087 -
Molecules (Basel, Switzerland) Sep 2022A new programed upper critical solution temperature-type thermoresponsive polymer was developed using water-soluble anionic polymer conjugates derived from...
A new programed upper critical solution temperature-type thermoresponsive polymer was developed using water-soluble anionic polymer conjugates derived from polyallylamine and phthalic acid with cleavage-induced phase transition property. Intrinsic charge inversion from anion to cation of the polymer side chain is induced through a side chain cleavage reaction in acidic aqueous media. With the progress of side chain cleavage under fixed external conditions, the polymer conjugates express a thermoresponsive property, followed by shifting a phase boundary due to the change in polymer composition. When the phase transition boundary eventually reached the examined temperature, phase transition occurs under fixed external conditions. Such new insight obtained in this study opens up the new concept of time-programed stimuli-responsive polymer possessing a cleavage-induced phase transition.
Topics: Anions; Phase Transition; Polymers; Stimuli Responsive Polymers; Temperature; Water
PubMed: 36144815
DOI: 10.3390/molecules27186082 -
Angewandte Chemie (International Ed. in... May 2022Active transport of ions uphill, creating a concentration gradient across a cell membrane, is essential for life. It remains a significant challenge to develop synthetic...
Active transport of ions uphill, creating a concentration gradient across a cell membrane, is essential for life. It remains a significant challenge to develop synthetic systems that allow active uphill transport. Here, a transport process fuelled by organometallic compounds is reported that creates a pH gradient. The hydrolysis reaction of Pt complexes results in the formation of aqua complexes that established rapid transmembrane movement ("flip-flop") of neutral Pt-OH species, leading to protonation of the OH group in the inner leaflet, generating OH ions, and so increasing the pH in the intravesicular solution. The organoplatinum complex effectively transports bound hydroxide ions across the membrane in a neutral complex. The initial net flow of the Pt complex into the vesicles generates a positive electric potential that can further drive uphill transport because the electric potential is opposed to the chemical potential of OH . The OH ions equilibrate with this transmembrane electric potential but cannot remove it due to the relatively low permeability of the charged species. As a result, effective hydroxide transport against its concentration gradient can be achieved, and multiple additions can continuously drive the generation of OH against its concentration gradient up to ΔpH>2. Moreover, the external addition of different anions can control the generation of OH depending on their anion binding affinity. When anions displayed very high binding affinities towards Pt compounds, such as halides, the external anions could dissipate the pH gradient. In contrast, a further pH increase was observed for weak binding anions, such as sulfate, due to the increase of positive electric potential.
Topics: Anions; Biological Transport; Hydrogen-Ion Concentration; Hydroxides; Kinetics; Membrane Potentials; Membrane Transport Proteins; Organoplatinum Compounds
PubMed: 35192743
DOI: 10.1002/anie.202116355 -
Molecular Pharmacology May 2022Formed by the choroid plexus epithelial (CPE) cells, the blood-cerebrospinal fluid barrier (BCSFB) plays an active role in removing drugs, toxins, and metabolic wastes...
Formed by the choroid plexus epithelial (CPE) cells, the blood-cerebrospinal fluid barrier (BCSFB) plays an active role in removing drugs, toxins, and metabolic wastes from the brain. Several organic cation and anion transporters are expressed in the CPE cells, but how they functionally mediate transepithelial transport of organic cations and anions remain unclear. In this study, we visualized the transcellular transport of fluorescent organic cation and organic anion probes using live tissue imaging in freshly isolated mouse choroid plexuses (CPs). The cationic probe, 4-[4-(dimethylamino)phenyl]-1-methylpyridinium iodide (IDT307) was transported into CPE cells at the apical membrane and highly accumulated in mitochondria. Consistent with the lack of expression of organic cation efflux transporters, there was little efflux of IDT307 into the blood capillary space. Furthermore, IDT307 uptake and intracellular accumulation was attenuated by approximately 70% in CP tissues from mice with targeted deletion of the plasma membrane monoamine transporter (Pmat). In contrast, the anionic probe fluorescein-methotrexate (FL-MTX) was rapidly transported across the CPE cells into the capillary space with little intracellular accumulation. Rifampicin, an inhibitor of organic anion transporting polypeptides (OATPs), completely blocked FL-MTX uptake into the CPE cells whereas MK-571, a pan-inhibitor of multidrug resistance associated proteins (MRPs), abolished basolateral efflux of FL-MTX. In summary, our results suggest distinct transcellular transport pathways for organic cations and anions at the BCSFB and reveal a pivotal role of PMAT, OATP and MRP transporters in organic cation and anion transport at the blood-cerebrospinal fluid interface. SIGNIFICANCE STATEMENT: Live tissue imaging revealed that while organic cations are transported from the cerebrospinal fluid (CSF) into the choroid plexus epithelial cells by plasma membrane monoamine transporter without efflux into the blood, amphipathic anions in the CSF are efficiently transported across the BCSFB through the collaborated function of apical organic anion transporting polypeptides and basolateral multidrug resistance associated proteins. These findings contribute to a mechanistic understanding of the molecular and cellular pathways for choroid plexus clearance of solutes from the brain.
Topics: Animals; Anions; Blood-Brain Barrier; Cations; Choroid Plexus; Membrane Transport Proteins; Mice; Multidrug Resistance-Associated Proteins; Organic Anion Transporters; Peptides; Transcytosis
PubMed: 35193935
DOI: 10.1124/molpharm.121.000439 -
ChemistryOpen Jun 2022Living cells often contain compartments with high concentration of charged biomolecules. A key question pertinent to the function of biomolecules is how water dynamics...
Living cells often contain compartments with high concentration of charged biomolecules. A key question pertinent to the function of biomolecules is how water dynamics are affected by interaction with charged molecules. Here, we study the dynamical behavior of water in an extreme condition, that is, in saturated salt solutions, where nearly all water molecules are located within the first hydration layer of ions. To facilitate disentangling the effects of cations and anions, our study is focused on alkali chloride solutions. Following a multi-nuclear NMR approach enabling direct monitoring of protons and the quadrupolar nuclei Li, O, Na, Cl, Rb and Cs, we investigate how the translational and rotational mobility of water molecules, chloride anion and corresponding cations are affected within the constrained environment of saturated solutions. Our results indicate that water molecules preserve a large level of mobility within saturated alkali chloride solutions that is significantly independent of adjacent ions.
Topics: Alkalies; Anions; Cations; Chlorides; Magnetic Resonance Spectroscopy; Sodium Chloride; Sodium Chloride, Dietary; Water
PubMed: 35642137
DOI: 10.1002/open.202200080 -
Molecular Pharmacology Sep 2022Human and animal malaria parasites increase their host erythrocyte permeability to a broad range of solutes as mediated by parasite-associated ion channels. Molecular...
Human and animal malaria parasites increase their host erythrocyte permeability to a broad range of solutes as mediated by parasite-associated ion channels. Molecular and pharmacological studies have implicated an essential role in parasite nutrient acquisition, but inhibitors suitable for development of antimalarial drugs are missing. Here, we generated a potent and specific drug lead using , a virulent human pathogen, and derivatives of MBX-2366, a nanomolar affinity pyridazinone inhibitor from a high-throughput screen. As this screening hit lacks the bioavailability and stability needed for in vivo efficacy, we synthesized 315 derivatives to optimize drug-like properties, establish target specificity, and retain potent activity against the parasite-induced permeability. Using a robust, iterative pipeline, we generated MBX-4055, a derivative active against divergent human parasite strains. MBX-4055 has improved oral absorption with acceptable in vivo tolerability and pharmacokinetics. It also has no activity against a battery of 35 human channels and receptors and is refractory to acquired resistance during extended in vitro selection. Single-molecule and single-cell patch-clamp indicate direct action on the plasmodial surface anion channel, a channel linked to parasite-encoded RhopH proteins. These studies identify pyridazinones as novel and tractable antimalarial scaffolds with a defined mechanism of action. SIGNIFICANCE STATEMENT: Because antimalarial drugs are prone to evolving resistance in the virulent human pathogen, new therapies are needed. This study has now developed a novel drug-like series of pyridazinones that target an unexploited parasite anion channel on the host cell surface, display excellent in vitro and in vivo ADME properties, are refractory to acquired resistance, and demonstrate a well defined mechanism of action.
Topics: Animals; Anions; Antimalarials; Erythrocytes; Folic Acid Antagonists; Humans; Nutrients; Plasmodium falciparum
PubMed: 35798366
DOI: 10.1124/molpharm.122.000549 -
Langmuir : the ACS Journal of Surfaces... Mar 2017The influence of inorganic anions on the photoreactivity and aggregation of titanium dioxide nanoparticles (NPs) was assessed by dosing carbonate, chloride, nitrate,...
The influence of inorganic anions on the photoreactivity and aggregation of titanium dioxide nanoparticles (NPs) was assessed by dosing carbonate, chloride, nitrate, phosphate, and sulfate as potassium salts at multiple concentrations. NP stability was monitored in terms of aggregate morphology and electrophoretic mobility (EPM). Aggregate size and fractal dimension were measured over time by laser diffraction, and the isoelectric point (IEP) as a function of anion and concentration was obtained by measuring EPM versus pH. Phosphate, carbonate, and to a lesser extent, sulfate decreased the IEP of TiO and stabilized NP suspensions owing to specific surface interactions, whereas this was not observed for nitrate and chloride. TiO NPs were exposed to UV-A radiation, and the photoreactivity was assessed by monitoring the production of reactive species over time both at the NP surface (photogenerated holes) and in the bulk solution (hydroxyl radicals) by observing their reactions with the selective probe compounds iodide and terephthalic acid, respectively. The generation of photogenerated holes and hydroxyl radicals was influenced by each inorganic anion to varying degrees. Carbonate and phosphate inhibited the oxidation of iodide, and this interaction was successfully described by a Langmuir-Hinshelwood mechanism and related to the characteristics of TiO aggregates. Chloride and nitrate do not specifically interact with TiO, and sulfate creates relatively weak interactions with the TiO surface such that no decrease in photogenerated hole reactivity was observed. A decrease in hydroxyl radical generation was observed for all inorganic anions. Quenching rate constants for the reaction of hydroxyl radicals with each inorganic anion do not provide a comprehensive explanation for the magnitude of this decrease, which arises from the interplay of several physicochemical phenomena. This work shows that the reactivity of NPs will be strongly influenced by the makeup of the waters they are released into. The impact of anion species on hydroxyl radical inhibition was as follows: carbonate > chloride > phosphate > nitrate > sulfate.
Topics: Anions; Catalysis; Isoelectric Point; Nanoparticles; Titanium
PubMed: 28238264
DOI: 10.1021/acs.langmuir.6b04116 -
RNA (New York, N.Y.) Jun 2010Although RNA molecules are highly negatively charged, anions have been observed bound to RNA in crystal structures. It has been proposed that anion binding sites found...
Although RNA molecules are highly negatively charged, anions have been observed bound to RNA in crystal structures. It has been proposed that anion binding sites found within isolated RNAs represent regions of the molecule that could be involved in intermolecular interactions, indicating potential contact points for negatively charged amino acids from proteins or phosphate groups from an RNA. Several types of anion binding sites have been cataloged based on available structures. However, currently there is no method for unambiguously assigning anions to crystallographic electron density, and this has precluded more detailed analysis of RNA-anion interaction motifs and their significance. We therefore soaked selenate into two different types of RNA crystals and used the anomalous signal from these anions to identify binding sites in these RNA molecules unambiguously. Examination of these sites and comparison with other suspected anion binding sites reveals features of anion binding motifs, and shows that selenate may be a useful tool for studying RNA-anion interactions.
Topics: Amino Acids; Anions; Binding Sites; Cations; Crystallography; Models, Molecular; Nucleic Acid Conformation; Proteins; RNA; Selenic Acid; Selenium Compounds; Sulfates; X-Ray Diffraction
PubMed: 20410239
DOI: 10.1261/rna.2072710 -
The Journal of Biological Chemistry Nov 2023Previous research of anion channelrhodopsins (ACRs) has been performed using cytoplasmic domain (CPD)-deleted constructs and therefore have overlooked the native...
Previous research of anion channelrhodopsins (ACRs) has been performed using cytoplasmic domain (CPD)-deleted constructs and therefore have overlooked the native functions of full-length ACRs and the potential functional role(s) of the CPD. In this study, we used the recombinant expression of full-length Guillardia theta ACR1 (GtACR1_full) for pH measurements in Pichia pastoris cell suspensions as an indirect method to assess its anion transport activity and for absorption spectroscopy and flash photolysis characterization of the purified protein. The results show that the CPD, which was predicted to be intrinsically disordered and possibly phosphorylated, enhanced NO transport compared to Cl transport, which resulted in the preferential transport of NO. This correlated with the extended lifetime and large accumulation of the photocycle intermediate that is involved in the gate-open state. Considering that the depletion of a nitrogen source enhances the expression of GtACR1 in native algal cells, we suggest that NO transport could be the natural function of GtACR1_full in algal cells.
Topics: Anions; Channelrhodopsins; Cryptophyta; Ion Transport; Nitrates
PubMed: 37778732
DOI: 10.1016/j.jbc.2023.105305