Kainate receptor
Kainate receptors, or kainic acid receptors, are ionotropic receptors that respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug first isolated from the red alga Digenea simplex, they have been traditionally classified as a non-NMDA-type receptor, along with the AMPA receptor. KARs are less understood than the other ionotropic glutamate receptors. Postsynaptic kainate receptors are involved in excitatory neurotransmission. Presynaptic kainate receptors have been implicated in inhibitory neurotransmission by modulating release of the inhibitory neurotransmitter GABA through a presynaptic mechanism. There are five types of kainate receptor subunits, GluR5, GluR6, GluR7, KA1 and KA2, which are similar to AMPA and NMDA receptor subunits and can be arranged in different ways to form a tetramer, a four subunit receptor. GluR5-7 can form homomers and heteromers, however, KA1 and KA2 can only form functional receptors by combining with one of the GluR5-7 subunits.
Since 2009 the kainate receptor subunits have been renamed to correspond with their gene name. Hence GluR5-7 are now GluK1-3 and KA1 and KA2 are GluK4 and GluK5 respectively; each KAR subunit begins with a 400-residue extracellular N-terminal domain, which plays a key role in assembly, followed by the first segment of the neurotransmitter-binding cleft, called S1. This segment passes through the cell membrane, forming the first of three membrane-spanning regions, M1; the M2 segment begins on the cytoplasmic face of the membrane, pushes into the cell membrane about half way, dips back out to the cytoplasm. This segment, termed the "p loop," determines the calcium permeability of the receptor. M2 turns into M3, another transmembrane segment which emerges on the extracellular face to complete the neurotransmitter binding site. M4 begins extracellularly, passes again through the membrane into the cytoplasm, forming the C-terminal of the protein; the ion channel formed by kainate receptors is permeable to potassium ions.
The single channel conductance of kainate receptor channels is similar to that of AMPA channels, at about 20 pS. However and decay times for postsynaptic potentials generated by KARs are slower than for AMPA postsynaptic potentials, their permeability to Ca2+ is very slight but varies with subunits and RNA editing at the tip of the p loop. Kainate receptors have both postsynaptic actions, they have a somewhat more limited distribution in the brain than AMPA and NMDA receptors, their function is less well defined. The convulsant kainic acid induces seizures, in part, by activation of kainate receptors containing the GluK2 subunit and probably via AMPA receptors Activation of kainate receptors containing the GluK1 subunit can induce seizures but deletion of this subunit does not reduce seizure susceptibility to kainate or in other seizure models. Deletion of either GluK1 or GluK2 does not alter kindling epileptogenesis or the expression of kindled seizures. Unlike AMPA receptors, kainate receptors play only a minor role in signaling at synapses.
Kainate receptors have a subtle role in synaptic plasticity, affecting the likelihood that the postsynaptic cell will fire in response to future stimulation. Activating kainate receptors in the presynaptic cell can affect the amount of neurotransmitters that are released This effect may occur and last for a long time, the effects of repetitive stimulation of KARs can be additive over time. 5-Iodowillardiine ATPA Domoic acid Glutamic acid – the endogenous agonist Kainic acid – a synthetic agonist after which the receptor is named LY-339,434 SYM-2081 CNQX DNQX Ethanol – non-selective NS102 Kynurenic acid – endogenous ligand Tezampanel – an AMPAR antagonist UBP-302 Theanine NMDA receptor AMPA receptor Long term potentiation Kainate+Receptor at the US National Library of Medicine Medical Subject Headings
Glycine receptor
The glycine receptor is the receptor of the amino acid neurotransmitter glycine. GlyR is an ionotropic receptor, it is one of the most distributed inhibitory receptors in the central nervous system and has important roles in a variety of physiological processes in mediating inhibitory neurotransmission in the spinal cord and brainstem. The receptor can be activated by a range of simple amino acids including glycine, β-alanine and taurine, can be selectively blocked by the high-affinity competitive antagonist strychnine. Caffeine is a competitive antagonist of GlyR. Gephyrin has been shown to be necessary for GlyR clustering at inhibitory synapses. GlyR is known to colocalize with the GABAA receptor on some hippocampal neurons; some exceptions can occur in the central nervous system where the GlyR α1 subunit and gephyrin, its anchoring protein, are not found in dorsal root ganglion neurons despite the presence of GABAA receptors. Strychnine-sensitive GlyRs are members of a family of ligand-gated ion channels.
Receptors of this family are arranged as five subunits surrounding a central pore, with each subunit composed of four α helical transmembrane segments. There are presently four known isoforms of the α-subunit of GlyR that are essential to bind ligands and a single β-subunit; the adult form of the GlyR is the heteromeric α1β receptor, believed to have a stoichiometry of three α1 subunits and two β subunits or four α1 subunits and one β subunit. The α-subunits are able to form functional homo-pentameric receptors in heterologous expression systems in African clawed frog's oocytes or mammalian cell lines, the α1 homomeric receptor is essential for studies of channel pharmacokinetics and pharmacodynamics. Auxiliary β subunit is unable to form functional channels without association with α subunits. However, previous reports have demonstrated that β subunit determines the synaptic localization of GlyRs, as well as the pharmacological profile of glycinergic currents Disruption of GlyR surface expression or reduced ability of expressed GlyRs to conduct chloride ions results in the rare neurological disorder, hyperekplexia.
The disorder is characterized by an exaggerated response to unexpected stimuli, followed by a temporary but complete muscular rigidity resulting in an unprotected fall. Chronic injuries as a result of the falls are symptomatic of the disorder. A mutation in GLRA1 is responsible for some cases of stiff person syndrome. Β-Alanine D-Alanine D-Serine Glycine Hypotaurine Ivermectin L-Alanine L-Proline L-Serine Milacemide Quisqualamine Sarcosine Taurine THC Ethanol Toluene Bicuculline Brucine Caffeine Levorphanol Picrotoxin Strychnine Tutin Glycine+Receptors at the US National Library of Medicine Medical Subject Headings
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determine the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as: pharmaceutical drugs, food additives, etc, it attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, whereas pharmacodynamics is the study of how the drug affects the organism. Both together influence dosing and adverse effects, as seen in PK/PD models. Pharmacokinetics describes how the body affects a specific xenobiotic/chemical after administration through the mechanisms of absorption and distribution, as well as the metabolic changes of the substance in the body, the effects and routes of excretion of the metabolites of the drug. Pharmacokinetic properties of chemicals are affected by the route of administration and the dose of administered drug.
These may affect the absorption rate. Models have been developed to simplify conceptualization of the many processes that take place in the interaction between an organism and a chemical substance. One of these, the multi-compartmental model, is the most used approximations to reality; the various compartments that the model is divided into are referred to as the ADME scheme: Liberation – the process of release of a drug from the pharmaceutical formulation. See IVIVC. Absorption – the process of a substance entering the blood circulation. Distribution – the dispersion or dissemination of substances throughout the fluids and tissues of the body. Metabolism – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites. Excretion – the removal of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue; the two phases of metabolism and excretion can be grouped together under the title elimination.
The study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. For this reason in order to comprehend the kinetics of a drug it is necessary to have detailed knowledge of a number of factors such as: the properties of the substances that act as excipients, the characteristics of the appropriate biological membranes and the way that substances can cross them, or the characteristics of the enzyme reactions that inactivate the drug. All these concepts can be represented through mathematical formulas that have a corresponding graphical representation; the use of these models allows an understanding of the characteristics of a molecule, as well as how a particular drug will behave given information regarding some of its basic characteristics such as its acid dissociation constant and solubility, absorption capacity and distribution in the organism. The model outputs for a drug can be used in industry or in the clinical application of pharmacokinetic concepts.
Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals and in veterinary medicine. The following are the most measured pharmacokinetic metrics: In pharmacokinetics, steady state refers to the situation where the overall intake of a drug is in dynamic equilibrium with its elimination. In practice, it is considered that steady state is reached when a time of 4 to 5 times the half-life for a drug after regular dosing is started; the following graph depicts a typical time course of drug plasma concentration and illustrates main pharmacokinetic metrics: Pharmacokinetic modelling is performed by noncompartmental or compartmental methods. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph. Compartmental methods estimate the concentration-time graph using kinetic models. Noncompartmental methods are more versatile in that they do not assume any specific compartmental model and produce accurate results acceptable for bioequivalence studies.
The final outcome of the transformations that a drug undergoes in an organism and the rules that determine this fate depend on a number of interrelated factors. A number of functional models have been developed in order to simplify the study of pharmacokinetics; these models are based on a consideration of an organism as a number of related compartments. The simplest idea is to think of an organism as only one homogenous compartment; this monocompartmental model presupposes that blood plasma concentrations of the drug are a true reflection of the drug's concentration in other fluids or tissues and that the elimination of the drug is directly proportional to the drug's concentration in the organism. However, these models do not always reflect the real situation within an organism. For example, not all body tissues have the same blood supply, so the distribution of the drug will be slower in these tissues than in others with a better blood supply. In addition, there are some tissues (s
Jmol
Jmol is computer software for molecular modelling chemical structures in 3-dimensions. Jmol returns a 3D representation of a molecule that may be used as a teaching tool, or for research e.g. in chemistry and biochemistry. It is written in the programming language Java, so it can run on the operating systems Windows, macOS, Unix, if Java is installed, it is free and open-source software released under a GNU Lesser General Public License version 2.0. A standalone application and a software development kit exist that can be integrated into other Java applications, such as Bioclipse and Taverna. A popular feature is an applet that can be integrated into web pages to display molecules in a variety of ways. For example, molecules can be displayed as ball-and-stick models, space-filling models, ribbon diagrams, etc. Jmol supports a wide range of chemical file formats, including Protein Data Bank, Crystallographic Information File, MDL Molfile, Chemical Markup Language. There is a JavaScript-only version, JSmol, that can be used on computers with no Java.
The Jmol applet, among other abilities, offers an alternative to the Chime plug-in, no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, the Sculpt mode. Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS 9. Jmol operates on a wide variety of platforms. For example, Jmol is functional in Mozilla Firefox, Internet Explorer, Google Chrome, Safari. Chemistry Development Kit Comparison of software for molecular mechanics modeling Jmol extension for MediaWiki List of molecular graphics systems Molecular graphics Molecule editor Proteopedia PyMOL SAMSON Official website Wiki with listings of websites and moodles Willighagen, Egon. "Fast and Scriptable Molecular Graphics in Web Browsers without Java3D". Doi:10.1038/npre.2007.50.1
Simplified molecular-input line-entry system
The simplified molecular-input line-entry system is a specification in the form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules; the original SMILES specification was initiated in the 1980s. It has since been extended. In 2007, an open standard called. Other linear notations include the Wiswesser line notation, ROSDAL, SYBYL Line Notation; the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. Acknowledged for their parts in the early development were "Gilman Veith and Rose Russo and Albert Leo and Corwin Hansch for supporting the work, Arthur Weininger and Jeremy Scofield for assistance in programming the system." The Environmental Protection Agency funded the initial project to develop SMILES. It has since been modified and extended by others, most notably by Daylight Chemical Information Systems.
In 2007, an open standard called "OpenSMILES" was developed by the Blue Obelisk open-source chemistry community. Other'linear' notations include the Wiswesser Line Notation, ROSDAL and SLN. In July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is considered to have the advantage of being more human-readable than InChI; the term SMILES refers to a line notation for encoding molecular structures and specific instances should be called SMILES strings. However, the term SMILES is commonly used to refer to both a single SMILES string and a number of SMILES strings; the terms "canonical" and "isomeric" can lead to some confusion when applied to SMILES. The terms are not mutually exclusive. A number of valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol. Algorithms have been developed to generate the same SMILES string for a given molecule; this SMILES is unique for each structure, although dependent on the canonicalization algorithm used to generate it, is termed the canonical SMILES.
These algorithms first convert the SMILES to an internal representation of the molecular structure. Various algorithms for generating canonical SMILES have been developed and include those by Daylight Chemical Information Systems, OpenEye Scientific Software, MEDIT, Chemical Computing Group, MolSoft LLC, the Chemistry Development Kit. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database; the original paper that described the CANGEN algorithm claimed to generate unique SMILES strings for graphs representing molecules, but the algorithm fails for a number of simple cases and cannot be considered a correct method for representing a graph canonically. There is no systematic comparison across commercial software to test if such flaws exist in those packages. SMILES notation allows the specification of configuration at tetrahedral centers, double bond geometry; these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES.
A notable feature of these rules is. The term isomeric SMILES is applied to SMILES in which isotopes are specified. In terms of a graph-based computational procedure, SMILES is a string obtained by printing the symbol nodes encountered in a depth-first tree traversal of a chemical graph; the chemical graph is first trimmed to remove hydrogen atoms and cycles are broken to turn it into a spanning tree. Where cycles have been broken, numeric suffix labels are included to indicate the connected nodes. Parentheses are used to indicate points of branching on the tree; the resultant SMILES form depends on the choices: of the bonds chosen to break cycles, of the starting atom used for the depth-first traversal, of the order in which branches are listed when encountered. Atoms are represented by the standard abbreviation of the chemical elements, in square brackets, such as for gold. Brackets may be omitted in the common case of atoms which: are in the "organic subset" of B, C, N, O, P, S, F, Cl, Br, or I, have no formal charge, have the number of hydrogens attached implied by the SMILES valence model, are the normal isotopes, are not chiral centers.
All other elements must be enclosed in brackets, have charges and hydrogens shown explicitly. For instance, the SMILES for water may be written as either O or. Hydrogen may be written as a separate atom; when brackets are used, the symbol H is added if the atom in brackets is bonded to one or more hydrogen, followed by the number of hydrogen atoms if greater than 1 by the sign + for a positive charge or by - for a negative charge. For example, for ammonium. If there is more than one charge, it is written as digit.
AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is an ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system. It has been traditionally classified as a non-NMDA-type receptor, along with the kainate receptor, its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a occurring agonist quisqualate and was only given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. AMPARs are found in many parts of the brain and are the most found receptor in the nervous system; the AMPA receptor GluA2 tetramer was the first glutamate receptor ion channel. AMPARs are composed of four types of subunits, designated as GluA1, GluA2, GluA3, GluA4, alternatively called GluRA-D2, which combine to form tetramers. Most AMPARs are heterotetrameric, consisting of symmetric'dimer of dimers' of GluA2 and either GluA1, GluA3 or GluA4.
Dimerization starts in the endoplasmic reticulum with the interaction of N-terminal LIVBP domains "zips up" through the ligand-binding domain into the transmembrane ion pore. The conformation of the subunit protein in the plasma membrane caused controversy for some time. While the amino acid sequence of the subunit indicated that there seemed to be four transmembrane domains, proteins interacting with the subunit indicated that the N-terminus seemed to be extracellular, while the C-terminus seemed to be intracellular. However, if each of the four transmembrane domains went all the way through the plasma membrane the two termini would have to be on the same side of the membrane, it was discovered that the second "transmembrane" domain does not in fact cross the membrane at all, but kinks back on itself within the membrane and returns to the intracellular side. When the four subunits of the tetramer come together, this second membranous domain forms the ion-permeable pore of the receptor. AMPAR subunits differ most in their C-terminal sequence, which determines their interactions with scaffolding proteins.
All AMPARs contain which PDZ domain they bind to differs. For example, GluA1 binds to SAP97 through SAP97's class I PDZ domain, while GluA2 binds to PICK1 and GRIP/ABP. Of note, AMPARs cannot directly bind to the common synaptic protein PSD-95 owing to incompatible PDZ domains, although they do interact with PSD-95 via stargazin. Phosphorylation of AMPARs can regulate channel localization and open probability. GluA1 has four known phosphorylation sites at serine 818, S831, threonine 840, S845. S818 is phosphorylated by protein kinase C, is necessary for long-term potentiation. S831 is phosphorylated by CaMKII and PKC during LTP, which helps deliver GluA1-containing AMPAR to the synapse, increases their single channel conductance; the T840 site was more discovered, has been implicated in LTD. S845 is phosphorylated by PKA which regulates its open probability; each AMPAR has one for each subunit. The binding site is believed to be formed by the N-terminal tail and the extracellular loop between transmembrane domains three and four.
When an agonist binds, these two loops move towards each other. The channel opens when two sites are occupied, increases its current as more binding sites are occupied. Once open, the channel may undergo rapid desensitization; the mechanism of desensitization is believed to be due to a small change in angle of one of the parts of the binding site, closing the pore. AMPARs open and close and are thus responsible for most of the fast excitatory synaptic transmission in the central nervous system; the AMPAR's permeability to calcium and other cations, such as sodium and potassium, is governed by the GluA2 subunit. If an AMPAR lacks a GluA2 subunit it will be permeable to sodium and calcium; the presence of a GluA2 subunit will always render the channel impermeable to calcium. This is determined by post-transcriptional modification — RNA editing — of the Q-to-R editing site of the GluA2 mRNA. Here, A→I editing alters the uncharged amino acid glutamine to the positively charged arginine in the receptor's ion channel.
The positively charged amino acid at the critical point makes it energetically unfavourable for calcium to enter the cell through the pore. All of the GluA2 subunits in CNS are edited to the GluA2 form; this means that the principal ions gated by AMPARs are sodium and potassium, distinguishing AMPARs from NMDA receptors, which permit calcium influx. Both AMPA and NMDA receptors, have an equilibrium potential near 0 mV; the prevention of calcium entry into the cell on activation of GluA2-containing AMPARs is proposed to guard against excitotoxicity. The subunit composition of the AMPAR is important for the way this receptor is modulated. If an AMPAR lacks GluA2 subunits it is susceptible to being blocked in a voltage-dependent manner by a class of molecules called polyamines. Thus, when the neuron is at a depolarized membrane potential, polyamines will block the AM
European Chemicals Agency
The European Chemicals Agency is an agency of the European Union which manages the technical and administrative aspects of the implementation of the European Union regulation called Registration, Evaluation and Restriction of Chemicals. ECHA is the driving force among regulatory authorities in implementing the EU's chemicals legislation. ECHA helps companies to comply with the legislation, advances the safe use of chemicals, provides information on chemicals and addresses chemicals of concern, it is located in Finland. The agency headed by Executive Director Bjorn Hansen, started working on 1 June 2007; the REACH Regulation requires companies to provide information on the hazards and safe use of chemical substances that they manufacture or import. Companies register this information with ECHA and it is freely available on their website. So far, thousands of the most hazardous and the most used substances have been registered; the information is technical but gives detail on the impact of each chemical on people and the environment.
This gives European consumers the right to ask retailers whether the goods they buy contain dangerous substances. The Classification and Packaging Regulation introduces a globally harmonised system for classifying and labelling chemicals into the EU; this worldwide system makes it easier for workers and consumers to know the effects of chemicals and how to use products safely because the labels on products are now the same throughout the world. Companies need to notify ECHA of the labelling of their chemicals. So far, ECHA has received over 5 million notifications for more than 100 000 substances; the information is available on their website. Consumers can check chemicals in the products. Biocidal products include, for example, insect disinfectants used in hospitals; the Biocidal Products Regulation ensures that there is enough information about these products so that consumers can use them safely. ECHA is responsible for implementing the regulation; the law on Prior Informed Consent sets guidelines for the import of hazardous chemicals.
Through this mechanism, countries due to receive hazardous chemicals are informed in advance and have the possibility of rejecting their import. Substances that may have serious effects on human health and the environment are identified as Substances of Very High Concern 1; these are substances which cause cancer, mutation or are toxic to reproduction as well as substances which persist in the body or the environment and do not break down. Other substances considered. Companies manufacturing or importing articles containing these substances in a concentration above 0,1% weight of the article, have legal obligations, they are required to inform users about the presence of the substance and therefore how to use it safely. Consumers have the right to ask the retailer whether these substances are present in the products they buy. Once a substance has been identified in the EU as being of high concern, it will be added to a list; this list is available on ECHA's website and shows consumers and industry which chemicals are identified as SVHCs.
Substances placed on the Candidate List can move to another list. This means that, after a given date, companies will not be allowed to place the substance on the market or to use it, unless they have been given prior authorisation to do so by ECHA. One of the main aims of this listing process is to phase out SVHCs where possible. In its 2018 substance evaluation progress report, ECHA said chemical companies failed to provide “important safety information” in nearly three quarters of cases checked that year. "The numbers show a similar picture to previous years" the report said. The agency noted that member states need to develop risk management measures to control unsafe commercial use of chemicals in 71% of the substances checked. Executive Director Bjorn Hansen called non-compliance with REACH a "worry". Industry group CEFIC acknowledged the problem; the European Environmental Bureau called for faster enforcement to minimise chemical exposure. European Chemicals Bureau Official website
