Modulation of recombinant human alpha 1 glycine receptor by flavonoids and gingerols

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Ulrike Breitinger ◽  
Heinrich Sticht ◽  
Hans-Georg Breitinger
Keyword(s):  
Binding Sites ◽  
Glycine Receptor ◽  
Hek293 Cells ◽  
Plant Metabolites ◽  
Secondary Plant Metabolites ◽  
Cell Current ◽  
Modulatory Sites ◽  
Induced Currents ◽  
Pore Lining ◽  
Related Compounds

Abstract The inhibitory glycine receptor (GlyR) is a principal mediator of fast synaptic inhibition in mammalian spinal cord, brainstem, and higher brain centres. Flavonoids are secondary plant metabolites that exhibit many beneficial physiological effects, including modulatory action on neuronal receptors. Using whole-cell current recordings from recombinant human α1 GlyRs, expressed in HEK293 cells, we compared the flavonols kaempferol and quercetin, the flavanone naringenin, the flavones apigenin and nobiletin, the isoflavone genistein, and two gingerols, 6-gingerol and 8-gingerol for their modulation of receptor currents. All compounds were inhibitors of the GlyR with IC50 values ranging between 9.3 ± 2.6 µM (kaempferol) and 46.7 ± 6.5 µM (genistein), following a mixed mode of inhibition. Co-application of two inhibitors revealed distinct binding sites for flavonoids and gingerols. Pore-lining mutants T258A and T258S were strongly inhibited by quercetin and naringenin, but not by 6-gingerol, confirming the existence of distinct binding sites for flavonoids and gingerols. Apigenin, kaempferol, nobiletin, naringenin and 6-gingerol showed biphasic action, potentiating glycine-induced currents at low concentration of both, modulator and glycine, and inhibiting at higher concentrations. Identification of distinct modulatory sites for flavonoids and related compounds may present pharmacological target sites and aid the discovery of novel glycinergic drugs.

scholarly journals A Picrotoxin-specific Conformational Change in the Glycine Receptor M2–M3 Loop

2005 ◽  
Vol 280 (43) ◽  
pp. 35836-35843 ◽  
Author(s):  
Rebecca Hawthorne ◽  
Joseph W. Lynch
Keyword(s):  
Conformational Change ◽  
Conformational Changes ◽  
Binding Sites ◽  
Glycine Receptor ◽  
Dissociation Rate ◽  
Open Probability ◽  
External Loop ◽  
Substituted Cysteine Accessibility ◽  
Specific Effects ◽  
Pore Lining

The external loop linking the M2 and M3 transmembrane domains is crucial for coupling agonist binding to channel gating in the glycine receptor chloride channel (GlyR). A substituted cysteine accessibility scan previously showed that glycine activation increased the surface accessibility of 6 contiguous residues (Arg271– Lys276) toward the N-terminal end of the homomeric α1 GlyR M2–M3 loop. In the present study we used a similar approach to determine whether the allosteric antagonist, picrotoxin, could impose conformational changes to this domain that cannot be induced by varying agonist concentrations alone. Picrotoxin slowed the reaction rate of a sulfhydryl-containing compound (MTSET) with A272C, S273C, and L274C. Before interpreting this as a picrotoxin-specific conformational change, it was necessary to eliminate the possibility of steric competition between picrotoxin and MTSET. Accordingly, we showed that picrotoxin and the structurally unrelated blocker, bilobalide, were both trapped in the R271C GlyR in the closed state and that a point mutation to the pore-lining Thr6′ residue abolished inhibition by both compounds. We also demonstrated that the picrotoxin dissociation rate was linearly related to the channel open probability. These observations constitute a strong case for picrotoxin binding in the pore. We thus conclude that the picrotoxin-specific effects on the M2–M3 loop are mediated allosterically. This suggests that the M2–M3 loop responds differently to the occupation of different binding sites.

General principle of primary and secondary plant metabolites: Biogenesis, metabolism, and extraction

2021 ◽  
pp. 3-23
Author(s):  
Charles Oluwaseun Adetunji ◽  
Santwana Palai ◽  
Chika Precious Ekwuabu ◽  
Chukwuebuka Egbuna ◽  
Juliana Bunmi Adetunji ◽  
...  
Keyword(s):  
General Principle ◽  
Plant Metabolites ◽  
Secondary Plant Metabolites ◽  
Secondary Plant

scholarly journals Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites

2005 ◽  
Vol 288 (2) ◽  
pp. F327-F333 ◽  
Author(s):  
Rémon A. M. H. Van Aubel ◽  
Pascal H. E. Smeets ◽  
Jeroen J. M. W. van den Heuvel ◽  
Frans G. M. Russel
Keyword(s):  
Binding Sites ◽  
Efflux Pump ◽  
Substrate Binding ◽  
Organic Anion ◽  
Apical Cell ◽  
Cell Uptake ◽  
Hek293 Cells ◽  
Hill Coefficient ◽  
Anion Transporter ◽  
Substrate Binding Sites

The end product of human purine metabolism is urate, which is produced primarily in the liver and excreted by the kidney through a well-defined basolateral blood-to-cell uptake step. However, the apical cell-to-urine efflux mechanism is as yet unidentified. Here, we show that the renal apical organic anion efflux transporter human multidrug resistance protein 4 (MRP4), but not apical MRP2, mediates ATP-dependent urate transport via a positive cooperative mechanism ( Km of 1.5 ± 0.3 mM, Vmax of 47 ± 7 pmol·mg−1·min−1, and Hill coefficient of 1.7 ± 0.2). In HEK293 cells overexpressing MRP4, intracellular urate levels were lower than in control cells. Urate inhibited methotrexate transport (IC50 of 235 ± 8 μM) by MRP4, did not affect cAMP transport, whereas cGMP transport was stimulated. Urate shifted cGMP transport by MRP4 from positive cooperativity ( Km and Vmax value of 180 ± 20 μM and 58 ± 4 pmol·mg−1·min−1, respectively, Hill coefficient of 1.4 ± 0.1) to single binding site kinetics ( Km and Vmax value of 2.2 ± 0.9 mM and 280 ± 50 pmol·mg−1·min−1, respectively). Finally, MRP4 could transport urate simultaneously with cAMP or cGMP. We conclude that human MRP4 is a unidirectional efflux pump for urate with multiple allosteric substrate binding sites. We propose MRP4 as a candidate transporter for urinary urate excretion and suggest that MRP4 may also mediate hepatic export of urate into the circulation, because of its basolateral expression in the liver.

scholarly journals Volatile terpenoids as potential drug leads in Alzheimer’s disease

2017 ◽  
Vol 15 (1) ◽  
pp. 332-343 ◽  
Author(s):  
Karolina A. Wojtunik-Kulesza ◽  
Katarzyna Targowska-Duda ◽  
Katarzyna Klimek ◽  
Grażyna Ginalska ◽  
Krzysztof Jóźwiak ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mtt Assay ◽  
Inhibitory Activity ◽  
Biological Activities ◽  
Plant Metabolites ◽  
Secondary Plant Metabolites ◽  
Docking Simulations ◽  
Ache Inhibitory Activity ◽  
Volatile Terpenoids

AbstractAlzheimer’s disease (AD) is by far the most prevalent of all known forms of dementia. Despite wide-spread research, the main causes of emergence and development of AD have not been fully recognized. Natural, low-molecular, lipophilic terpenoids constitute an interesting group of secondary plant metabolites, that exert biological activities of possible use in the prevention and treatment of AD. In order to identify secondary metabolites possessing both antioxidant activity and the potential to increase the level of acetylcholine, selected terpenoids have been screened for possible acetylcholinesterase inhibitory activity by use of two methods, namely Marston (chromatographic assay) and Ellman (spectrophotometric assay). In order to describe the interaction between terpenes and AChE active gorge, molecular docking simulations were performed. Additionally, all analyzed terpenes were also evaluated for their cytotoxic properties against two normal cell lines using MTT assay. The obtained results show that: carvone (6), pulegone (8) and γ-terpinene (7) possess desirable AChE inhibitory activity. MTT assay revealed low or lack of cytotoxicity of these metabolites. Thus, among the investigated terpenes, carvone (6), pulegone (8) and y-terpinene (7) can be recognized as compounds with most promising activities in the development of multi-target directed ligands.

The effect of plant metabolites on coronaviruses: A comprehensive review focusing on their IC50 values and molecular docking scores

2021 ◽  
Vol 21 ◽  
Author(s):  
Parastou Farshi ◽  
Eda Ceren Kaya ◽  
Fataneh Hashempour-Baltork ◽  
Kianoush Khosravi-Darani
Keyword(s):  
Molecular Docking ◽  
Inhibitory Effect ◽  
Organosulfur Compounds ◽  
Amino Acid Residues ◽  
Plant Metabolites ◽  
Primary Metabolites ◽  
Secondary Plant Metabolites ◽  
Protein Receptors ◽  
Ic50 Values ◽  
Natural Drugs

: Coronaviruses have caused worldwide outbreaks in different periods. SARS (severe acute respiratory syndrome), was the first emerged virus from this family, followed by MERS (Middle East respiratory syndrome) and SARS-CoV-2 (2019-nCoV or COVID 19), which is newly emerged. Many studies have been conducted on the application of chemical and natural drugs for treating these coronaviruses and they are mostly focused on inhibiting the proteases of viruses or blocking their protein receptors through binding to amino acid residues. Among many substances which are introduced to have an inhibitory effect against coronaviruses through the mentioned pathways, natural components are of specific interest. Secondary and primary metabolites from plants, are considered as potential drugs to have an inhibitory effect on coronaviruses. IC50 value (the concentration in which there is 50% loss in enzyme activity), molecular docking score and binding energy are parameters to understand the ability of metabolites to inhibit the specific virus. In this study we did a review of 154 papers on the effect of plant metabolites on different coronaviruses and data of their IC50 values, molecular docking scores and inhibition percentages are collected in tables. Secondary plant metabolites such as polyphenol, alkaloids, terpenoids, organosulfur compounds, saponins and saikosaponins, lectins, essential oil, and nicotianamine, and primary metabolites such as vitamins are included in this study.

Chapter 5 Secondary Plant Metabolites: Mechanisms and Roles in Insect Pest Management

2016 ◽  
pp. 135-168
Author(s):  
Tamoghna Saha ◽  
Nithya C. ◽  
Shyambabu S. ◽  
Kiran Kumari ◽  
S. N. Ray ◽  
...  
Keyword(s):  
Pest Management ◽  
Insect Pest ◽  
Insect Pest Management ◽  
Plant Metabolites ◽  
Secondary Plant Metabolites ◽  
Secondary Plant

scholarly journals MEDICINALLY IMPORTANT PLANT CLEOME GYNANDRA: A PHYTOCHEMICAL AND PHARMACOLOGICAL EXPLANATION

2018 ◽  
Vol 11 (1) ◽  
pp. 21
Author(s):  
Partha Pradip Adhikari ◽  
Satya Bhusan Paul
Keyword(s):  
Radical Scavenging ◽  
Eastern Region ◽  
Plant Metabolites ◽  
Traditional Use ◽  
Secondary Plant Metabolites ◽  
North East India ◽  
North East ◽  
Cleome Gynandra ◽  
North Eastern ◽  
Different Parts

  Cleome genus includes 601 plant species from the family Cleomaceae. Of more than 600 plants, 206 (34.3%) plants are having accepted species names. Cleome gynandra Linn. is a well-known medicinal plant with traditional and pharmacological importance. A good number of secondary plant metabolites have also been isolated from different parts of C. gynandra. Our investigation confirms two mutant varieties of C. gynandra exists in India. Accordingly, the objective of this study was designed to critically evaluate the pharmacological and phytochemical evaluation of C. gynandra of two mutant variety, to provide a consolidated platform for research potential of both the mutant varieties of C. gynandra. Careful scrutiny reveals that the plant possesses a huge range pharmacological applications, such as anti-inflammatory, free radical scavenging, anticancerous, immunomodulator, and antidiabetic agents. To arrive its pharmacological importance the published papers also shown an enormous amount of phytochemicals endorsement. Scientific perusal reveals different parts of the plant has an immense medicinal importance which proofs its traditional use round the glove. But in North-Eastern region of India, the same plant abundantly found in pink mutant variety. To date, there is not much research investigation for this mutant variety to validate its pharmacological importance. Therefore, research needs to scrutinize and compare the medicinal claims of the pink mutant variety in the bio-diverse region of North-East India.

scholarly journals Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity

2018 ◽  
Vol 115 (42) ◽  
pp. 10672-10677 ◽  
Author(s):  
Stephanie A. Heusser ◽  
Marie Lycksell ◽  
Xueqing Wang ◽  
Sarah E. McComas ◽  
Rebecca J. Howard ◽  
...  
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Inhibitory Effect ◽  
Allosteric Modulation ◽  
Bacterial Protein ◽  
Detailed Model ◽  
Differential Motion ◽  
State Dependent ◽  
The Common ◽  
Pore Lining

Theories of general anesthesia have shifted in focus from bulk lipid effects to specific interactions with membrane proteins. Target receptors include several subtypes of pentameric ligand-gated ion channels; however, structures of physiologically relevant proteins in this family have yet to define anesthetic binding at high resolution. Recent cocrystal structures of the bacterial protein GLIC provide snapshots of state-dependent binding sites for the common surgical agent propofol (PFL), offering a detailed model system for anesthetic modulation. Here, we combine molecular dynamics and oocyte electrophysiology to reveal differential motion and modulation upon modification of a transmembrane binding site within each GLIC subunit. WT channels exhibited net inhibition by PFL, and a contraction of the cavity away from the pore-lining M2 helix in the absence of drug. Conversely, in GLIC variants exhibiting net PFL potentiation, the cavity was persistently expanded and proximal to M2. Mutations designed to favor this deepened site enabled sensitivity even to subclinical concentrations of PFL, and a uniquely prolonged mode of potentiation evident up to ∼30 min after washout. Dependence of these prolonged effects on exposure time implicated the membrane as a reservoir for a lipid-accessible binding site. However, at the highest measured concentrations, potentiation appeared to be masked by an acute inhibitory effect, consistent with the presence of a discrete, water-accessible site of inhibition. These results support a multisite model of transmembrane allosteric modulation, including a possible link between lipid- and receptor-based theories that could inform the development of new anesthetics.

scholarly journals Antitoxic, Antifungal and Phytochemical Analysis of Medicinal Compounds of Guiera senegalensis Leaves

2020 ◽  
Vol 10 (2) ◽  
pp. 148-152
Author(s):  
Z.M. Anka ◽  
Vijender Singh ◽  
S.N. Gimba ◽  
Gunjan Singh
Keyword(s):  
Antifungal Activity ◽  
Phytochemical Analysis ◽  
Desert Area ◽  
Plant Metabolites ◽  
Secondary Plant Metabolites ◽  
Chemical Substances ◽  
Western Africa ◽  
Traditional Medicinal Plants ◽  
The World ◽  
Guiera Senegalensis

Millions of people in the world depend on traditional medicinal plants for treatment of many diseases.  They have curative properties due to presence of various complex chemical substances of different composition, which are found as secondary plant metabolites in one or more parts of these plants. These plant metabolites according to their composition are grouped as flavonoids, tannins, alkaloids, saponins etc. Guiera senegalensis(Gs), which grows in abundance in semi-desert area of Western Africa such as Nigeria, has been used for treating specific diseases and wounds. The study is carried out to investigate the phytochemical analysis, toxicity, and the antifungal activity of Gs leaves extract. Keywords: Guiera senegalensis, Antifungal activity, Brine shrimp, toxicity, phytochemical analysis;

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