scholarly journals A Model for Predicting Cation Selectivity and Permeability in AMPA and NMDA Receptors Based on Receptor Subunit Composition

2021 ◽  
Vol 13 ◽  
Author(s):  
Sampath Kumar ◽  
Sanjay S. Kumar
Keyword(s):  
Experimental Data ◽  
Divalent Cations ◽  
Ion Selectivity ◽  
Gene Families ◽  
Subunit Composition ◽  
Receptor Subunit ◽  
Cation Selectivity ◽  
Subunit Stoichiometry ◽  
Ampa And Nmda Receptors

Glutamatergic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartate) receptors are implicated in diverse functions ranging from synaptic plasticity to cell death. They are heterotetrameric proteins whose subunits are derived from multiple distinct gene families. The subunit composition of these receptors determines their permeability to monovalent and/or divalent cations, but it is not entirely clear how this selectivity arises in native and recombinantly-expressed receptor populations. By analyzing the sequence of amino acids lining the selectivity filters within the pore forming membrane helices (M2) of these subunits and by correlating subunit stoichiometry of these receptors with their ability to permeate Na+ and/or Ca2+, we propose here a mathematical model for predicting cation selectivity and permeability in these receptors. The model proposed is based on principles of charge attractivity and charge neutralization within the pore forming region of these receptors; it accurately predicts and reconciles experimental data across various platforms including Ca2+ permeability of GluA2-lacking AMPARs and ion selectivity within GluN3-containing di- and tri-heteromeric NMDARs. Additionally, the model provides insights into biophysical mechanisms regulating cation selectivity and permeability of these receptors and the role of various subunits in these processes.

scholarly journals Tuning the ion selectivity of glutamate transporter–associated uncoupled conductances

2016 ◽  
Vol 148 (1) ◽  
pp. 13-24 ◽  
Author(s):  
Rosemary J. Cater ◽  
Robert J. Vandenberg ◽  
Renae M. Ryan
Keyword(s):  
Excitatory Amino Acid ◽  
Ion Selectivity ◽  
Glutamate Transporter ◽  
Amino Acid Transporters ◽  
Primary Role ◽  
Cation Selectivity ◽  
Anion Selectivity ◽  
Transport Domain ◽  
Cl Conductance

The concentration of glutamate within a glutamatergic synapse is tightly regulated by excitatory amino acid transporters (EAATs). In addition to their primary role in clearing extracellular glutamate, the EAATs also possess a thermodynamically uncoupled Cl− conductance. This conductance is activated by the binding of substrate and Na+, but the direction of Cl− flux is independent of the rate or direction of substrate transport; thus, the two processes are thermodynamically uncoupled. A recent molecular dynamics study of the archaeal EAAT homologue GltPh (an aspartate transporter from Pyrococcus horikoshii) identified an aqueous pore at the interface of the transport and trimerization domains, through which anions could permeate, and it was suggested that an arginine residue at the most restricted part of this pathway might play a role in determining anion selectivity. In this study, we mutate this arginine to a histidine in the human glutamate transporter EAAT1 and investigate the role of the protonation state of this residue on anion selectivity and transporter function. Our results demonstrate that a positive charge at this position is crucial for determining anion versus cation selectivity of the uncoupled conductance of EAAT1. In addition, because the nature of this residue influences the turnover rate of EAAT1, we reveal an intrinsic link between the elevator movement of the transport domain and the Cl− channel.

scholarly journals Divalent Cation Modulation of Ion Permeation in TMEM16 Proteins

2021 ◽  
Vol 22 (4) ◽  
pp. 2209
Author(s):  
Dung M. Nguyen ◽  
Hwoi Chan Kwon ◽  
Tsung-Yu Chen
Keyword(s):  
Alkaline Earth ◽  
Divalent Cations ◽  
Transmembrane Protein ◽  
Ion Selectivity ◽  
Physiological Role ◽  
Ion Permeation ◽  
Membrane Phospholipids ◽  
Anion Channels ◽  
Head Groups

Intracellular divalent cations control the molecular function of transmembrane protein 16 (TMEM16) family members. Both anion channels (such as TMEM16A) and phospholipid scramblases (such as TMEM16F) in this family are activated by intracellular Ca2+ in the low µM range. In addition, intracellular Ca2+ or Co2+ at mM concentrations have been shown to further potentiate the saturated Ca2+-activated current of TMEM16A. In this study, we found that all alkaline earth divalent cations in mM concentrations can generate similar potentiation effects in TMEM16A when applied intracellularly, and that manipulations thought to deplete membrane phospholipids weaken the effect. In comparison, mM concentrations of divalent cations minimally potentiate the current of TMEM16F but significantly change its cation/anion selectivity. We suggest that divalent cations may increase local concentrations of permeant ions via a change in pore electrostatic potential, possibly acting through phospholipid head groups in or near the pore. Monovalent cations appear to exert a similar effect, although with a much lower affinity. Our findings resolve controversies regarding the ion selectivity of TMEM16 proteins. The physiological role of this mechanism, however, remains elusive because of the nearly constant high cation concentrations in cytosols.

Actions of anesthetics on ligand‐gated ion channels: role of receptor subunit composition

1995 ◽  
Vol 9 (14) ◽  
pp. 1454-1462 ◽  
Author(s):  
R. Adron Harris ◽  
S. John Mihic ◽  
Jo Ellen Dildy‐Mayfield ◽  
Tina K. Machu
Keyword(s):  
Ion Channels ◽  
Subunit Composition ◽  
Receptor Subunit ◽  
Gated Ion Channels ◽  
Ligand Gated Ion Channels

scholarly journals Divalent Cation Selectivity Is a Function of Gating in Native and Recombinant Cyclic Nucleotide–gated Ion Channels from Retinal Photoreceptors

1999 ◽  
Vol 113 (6) ◽  
pp. 799-818 ◽  
Author(s):  
David H. Hackos ◽  
Juan I. Korenbrot
Keyword(s):  
Divalent Cation ◽  
Cyclic Nucleotide ◽  
Divalent Cations ◽  
Ion Selectivity ◽  
Ion Concentration ◽  
Cone Photoreceptors ◽  
Cation Selectivity ◽  
Channel Opening ◽  
Α And Β Subunits ◽  
Α Subunits

The selectivity of Ca2+ over Na+ is ∼3.3-fold larger in cGMP-gated channels of cone photoreceptors than in those of rods when measured under saturating cGMP concentrations, where the probability of channel opening is 85–90%. Under physiological conditions, however, the probability of opening of the cGMP-gated channels ranges from its largest value in darkness of 1–5% to essentially zero under continuous, bright illumination. We investigated the ion selectivity of cGMP-gated channels as a function of cyclic nucleotide concentration in membrane patches detached from the outer segments of rod and cone photoreceptors and have found that ion selectivity is linked to gating. We determined ion selectivity relative to Na+ (PX/PNa) from the value of reversal potentials measured under ion concentration gradients. The selectivity for Ca2+ over Na+ increases continuously as the probability of channel opening rises. The dependence of PCa/PNa on cGMP concentration, in both rods and cones, is well described by the same Hill function that describes the cGMP dependence of current amplitude. At the cytoplasmic cGMP concentrations expected in dark-adapted intact photoreceptors, PCa/PNa in cone channels is ∼7.4-fold greater than that in rods. The linkage between selectivity and gating is specific for divalent cations. The selectivity of Ca2+ and Sr2+ changes with cGMP concentration, but the selectivity of inorganic monovalent cations, Cs+ and NH4+, and organic cations, methylammonium+ and dimethylammonium+, is invariant with cGMP. Cyclic nucleotide–gated channels in rod photoreceptors are heteromeric assemblies of α and β subunits. The maximal PCa/PNa of channels formed from α subunits of bovine rod channels is less than that of heteromeric channels formed from α and β subunits. In addition, Ca2+ is a more effective blocker of channels formed by α subunits than of channels formed by α and β subunits. The cGMP-dependent shift in divalent cation selectivity is a property of αβ channels and not of channels formed from α subunits alone.

scholarly journals Ion selectivity and current saturation in inward-rectifier K+ channels

2012 ◽  
Vol 139 (2) ◽  
pp. 145-157 ◽  
Author(s):  
Lei Yang ◽  
Johan Edvinsson ◽  
Henry Sackin ◽  
Lawrence G. Palmer
Keyword(s):  
Divalent Cations ◽  
Ion Selectivity ◽  
Monovalent Cation ◽  
Inward Rectifier ◽  
Ion Concentration ◽  
K Channel ◽  
Cation Selectivity ◽  
Current Saturation ◽  
Lower Permeability ◽  
A Site

We investigated the features of the inward-rectifier K channel Kir1.1 (ROMK) that underlie the saturation of currents through these channels as a function of permeant ion concentration. We compared values of maximal currents and apparent Km for three permeant ions: K+, Rb+, and NH4+. Compared with K+ (imax = 4.6 pA and Km = 10 mM at −100 mV), Rb+ had a lower permeability, a lower imax (1.8 pA), and a higher Km (26 mM). For NH4+, the permeability was reduced more with smaller changes in imax (3.7 pA) and Km (16 mM). We assessed the role of a site near the outer mouth of channel in the saturation process. This site could be occupied by either permeant ions or low-affinity blocking ions such as Na+, Li+, Mg2+, and Ca2+ with similar voltage dependence (apparent valence, 0.15–0.20). It prefers Mg2+ over Ca2+ and has a monovalent cation selectivity, based on the ability to displace Mg2+, of K+ > Li+ ∼ Na+ > Rb+ ∼ NH4+. Conversely, in the presence of Mg2+, the Km for K+ conductance was substantially increased. The ability of Mg2+ to block the channels was reduced when four negatively charged amino acids in the extracellular domain of the channel were mutated to neutral residues. The apparent Km for K+ conduction was unchanged by these mutations under control conditions but became sensitive to the presence of external negative charges when residual divalent cations were chelated with EDTA. The results suggest that a binding site in the outer mouth of the pore controls current saturation. Permeability is more affected by interactions with other sites within the selectivity filter. Most features of permeation (and block) could be simulated by a five-state kinetic model of ion movement through the channel.

РОЛЬ ФИЗИЧЕСКОЙ РАЗМИНКИ В ПОДГОТОВКЕ К ТРЕНИРОВОЧНЫМ ЗАНЯТИЯМ И СОРЕВНОВАНИЯМ ШАХМАТИСТОВ БГУ

2019 ◽  
pp. 63-65
Author(s):  
Судоргин Е.П. ◽  
Карсакова И.Н.
Keyword(s):  
Experimental Data ◽  
Sport Performance ◽  
Warm Up ◽  
Physical Exercises ◽  
Methods Of Evaluation ◽  
Mental Fitness ◽  
Physical Preparation ◽  
Tools And Methods

Аннотация: О роли разминки перед тренировкой и соревнованиями написано много научных статьей и диссертаций. Ещё больше о значимости физической подготовки спортсменов, в том числе и шахматистов. В то же время авторы считают, что вопросу физической подготовки шахматистов и в частности разминке в научной и научно-методической литературе уделяется недостаточно внимания. В своей статье авторы приводят собственные экспериментальные данные о влиянии физических упражнений (разминки) на умственную работоспособность студентов-шахматистов БГУ и как следствие на спортивные результаты команды. Ключевые слова: Шахматы, разминка, умственная работоспособность, средства и методы разминки, методы оценки результатов. Аннотация: Машыгуунун жана мелдештердин алдында даярдоонун ролу жөнүндө көптөгөн илимий макала жана диссертация жазылган. Ошондой эле илимий жана илимий-методикалык адабияттарда шахматка даярдоого көп көңүл бурулбай жатат. Макаланын авторлору шахмат ойногон студенттерге физикалык көнүгүүлөрдүн тийгизген таасири жөнүндө өздөрүнүн эксперименталдык маалыматтарын көргөзүштү. Түйүндүү сөздөр: Шахмат, акыл-дарамет, курулуштар жана ыкмалар, баа берүү жыйынтыгы боюнча кабыл алынат. Abstract: on the role of warm-up before training and competitions written many scientific articles and theses. More about the significance of the physical preparation of athletes, including players. At the same time, the authors believe that the issue of fit- ness players and in particular workout in scientific and scientific-methodical literature neglected. In his article the authors cite their own experimental data on the influence of physical exercises (warm-up) on the mental fitness of students-BSU players and as a result the sport performance team. Keywords: chess, warm-up, mental fitness, workout tools and methods, methods of evaluation results.

scholarly journals Oxidation of Terpenoids to Achieve High-Value Flavor and Fragrances—Questioning Microalgae Oxidative Capabilities in the Biotransformation of the Sesquiterpene Valencene and of Selected Natural Apocarotenoids

Chemistry ◽  
2021 ◽  
Vol 3 (3) ◽  
pp. 821-830
Author(s):  
Davide De Simeis ◽  
Stefano Serra ◽  
Alessandro Di Fonzo ◽  
Francesco Secundo
Keyword(s):  
Experimental Data ◽  
Natural Products ◽  
Aqueous Medium ◽  
Photochemical Reaction ◽  
Substrate Oxidation ◽  
Market Size ◽  
Chlorella Sp ◽  
General Opinion ◽  
Natural Way

Natural flavor and fragrance market size is expected to grow steadily due to the rising consumer demand of natural ingredients. This market request is guided by the general opinion that the production of natural compounds leads to a reduction of pollution, with inherent advantages for the environment and people’s health. The biotransformation reactions have gained high relevance in the production of natural products. In this context, few pieces of research have described the role of microalgae in the oxidation of terpenoids. In this present study, we questioned the role of microalgal based oxidation in the synthesis of high-value flavors and fragrances. This study investigated the role of three different microalgae strains, Chlorella sp. (211.8b and 211.8p) and Chlorococcum sp. (JB3), in the oxidation of different terpenoid substrates: α-ionone, β-ionone, theaspirane and valencene. Unfortunately, the experimental data showed that the microalgal strains used are not responsible for the substrate oxidation. In fact, our experiments demonstrate that the transformation of the four starting compounds is a photochemical reaction that involves the oxygen as oxidant. Even though these findings cast a shadow on the use of these microorganisms for an industrial purpose, they open a new possible strategy to easily obtain nootkatone in a natural way by just using an aqueous medium, oxygen and light.

The role of N-methyl-d -aspartate receptor subunit NR2B in spinal cord in cancer pain

2010 ◽  
Vol 14 (5) ◽  
pp. 496-502 ◽  
Author(s):  
XiaoPing Gu ◽  
Juan Zhang ◽  
ZhengLiang Ma ◽  
JunHua Wang ◽  
XiaoFang Zhou ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Cancer Pain ◽  
Receptor Subunit ◽  
Aspartate Receptor

scholarly journals Elucidating the Complex Interactions between Stress and Epileptogenic Pathways

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Aaron R. Friedman ◽  
Luisa P. Cacheaux ◽  
Sebastian Ivens ◽  
Daniela Kaufer
Keyword(s):  
Experimental Data ◽  
Blood Brain Barrier ◽  
Inflammatory Cytokine ◽  
Stress Hormones ◽  
Brain Barrier ◽  
Barrier Dysfunction ◽  
Complex Interactions ◽  
Narrow Focus ◽  
Analytical Tools

Clinical and experimental data suggest that stress contributes to the pathology of epilepsy. We review mechanisms by which stress, primarily via stress hormones, may exacerbate epilepsy, focusing on the intersection between stress-induced pathways and the progression of pathological events that occur before, during, and after the onset of epileptogenesis. In addition to this temporal nuance, we discuss other complexities in stress-epilepsy interactions, including the role of blood-brain barrier dysfunction, neuron-glia interactions, and inflammatory/cytokine pathways that may be protective or damaging depending on context. We advocate the use of global analytical tools, such as microarray, in support of a shift away from a narrow focus on seizures and towards profiling the complex, early process of epileptogenesis, in which multiple pathways may interact to dictate the ultimate onset of chronic, recurring seizures.

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