Nicotinic acetylcholine receptor
Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors respond to drugs, including the nicotinic receptor agonist nicotine, they are found in the central and peripheral nervous system and many other tissues of many organisms, including humans. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. In insects, the cholinergic system is limited to the central nervous system; the nicotinic receptors are considered cholinergic receptors.
Nicotinic receptors get their name from nicotine, which does not stimulate the muscarinic acetylcholine receptor, but instead selectively binds to the nicotinic receptor. The muscarinic acetylcholine receptor gets its name from a chemical that selectively attaches to that receptor — muscarine. Acetylcholine itself binds to both nicotinic acetylcholine receptors; as ionotropic receptors, nAChRs are directly linked to ion channels. New evidence suggests that these receptors can use second messengers in some cases. Nicotinic acetylcholine receptors are the best-studied of the ionotropic receptors. Since nicotinic receptors help transmit outgoing signals for the sympathetic and parasympathetic systems, nicotinic receptor antagonists such as hexamethonium interfere with the transmission of these signals. Thus, for example, nicotinic receptor antagonists interfere with the baroreflex that corrects changes in blood pressure by sympathetic and parasympathetic stimulation of the heart. Nicotinic receptors, with a molecular mass of 290 kDa, are made up of five subunits, arranged symmetrically around a central pore.
Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. They possess similarities with GABAA receptors, glycine receptors, the type 3 serotonin receptors, or the signature Cys-loop proteins. In vertebrates, nicotinic receptors are broadly classified into two subtypes based on their primary sites of expression: muscle-type nicotinic receptors and neuronal-type nicotinic receptors. In the muscle-type receptors, found at the neuromuscular junction, receptors are either the embryonic form, composed of α1, β1, γ, δ subunits in a 2:1:1:1 ratio, or the adult form composed of α1, β1, δ, ε subunits in a 2:1:1:1 ratio; the neuronal subtypes are various homomeric or heteromeric combinations of twelve different nicotinic receptor subunits: α2−α10 and β2−β4. Examples of the neuronal subtypes include: 32, 23, 23, α4α6β32, 5, many others. In both muscle-type and neuronal-type receptors, the subunits are similar to one another in the hydrophobic regions. A number of electron microscopy and x-ray crystallography studies have provided high resolution structural information for muscle and neuronal nAChRs and their binding domains.
As with all ligand-gated ion channels, opening of the nAChR channel pore requires the binding of a chemical messenger. Several different terms are used to refer to the molecules that bind receptors, such as ligand, agonist, or transmitter; as well as the endogenous agonist acetylcholine, agonists of the nAChR include nicotine and choline. Nicotinic antagonists that block the receptor include mecamylamine, dihydro-β-erythroidine, hexamethonium. In muscle-type nAChRs, the acetylcholine binding sites are located at the α and either ε or δ subunits interface. In neuronal nAChRs, the binding site is located at the interface of an α and a β subunit or between two α subunits in the case of α7 receptors; the binding site is located in the extracellular domain near the N terminus. When an agonist binds to the site, all present subunits undergo a conformational change and the channel is opened and a pore with a diameter of about 0.65 nm opens. Nicotinic AChRs may exist in different interconvertible conformational states.
Binding of an agonist stabilises the desensitised states. In normal physiological conditions, the receptor needs two molecules of ACh to open. Opening of the channel allows positively charged ions to move across it; the net flow of positively charged ions is inward. The nAChR is a non-selective cation channel, meaning that several different positively charged ions can cross through, it is permeable to Na+ and K+, with some subunit combinations that are permeable to Ca2+. The amount of sodium and potassium the channels allow through their pores varies from 50–110 pS, with the conductance depending on the specific subunit composition as well as the permeant ion. Many neuronal nAChRs can affect the release of other neurotransmitters; the channel opens and tends to remain open until the agonist diffuses away, which takes about 1 millisecond. However, AChRs can spontaneously open with no ligands bound or can spontaneously close with ligands bound, mutations in the channel can shift the likelihood of either event.
Therefore, ACh binding changes the probability of pore opening. The nAChR is unable to bind ACh. The
The adenosine receptors are a class of purinergic G protein-coupled receptors with adenosine as endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; the adenosine receptors are known for their antagonists caffeine and theophylline, whose action on the receptors produces the stimulating effects of coffee and chocolate. Each type of adenosine receptor has different functions. For instance, both A1 receptors and A2A play roles in the heart, regulating myocardial oxygen consumption and coronary blood flow, while the A2A receptor has broader anti-inflammatory effects throughout the body; these two receptors have important roles in the brain, regulating the release of other neurotransmitters such as dopamine and glutamate, while the A2B and A3 receptors are located peripherally and are involved in processes such as inflammation and immune responses. Most older compounds acting on adenosine receptors are nonselective, with the endogenous agonist adenosine being used in hospitals as treatment for severe tachycardia, acting directly to slow the heart through action on all four adenosine receptors in heart tissue, as well as producing a sedative effect through action on A1 and A2A receptors in the brain.
Xanthine derivatives such as caffeine and theophylline act as non-selective antagonists at A1 and A2A receptors in both heart and brain and so have the opposite effect to adenosine, producing a stimulant effect and rapid heart rate. These compounds act as phosphodiesterase inhibitors, which produces additional anti-inflammatory effects, makes them medically useful for the treatment of conditions such as asthma, but less suitable for use in scientific research. Newer adenosine receptor agonists and antagonists are much more potent and subtype-selective, have allowed extensive research into the effects of blocking or stimulating the individual adenosine receptor subtypes, now resulting in a new generation of more selective drugs with many potential medical uses; some of these compounds are still derived from adenosine or from the xanthine family, but researchers in this area have discovered many selective adenosine receptor ligands that are structurally distinct, giving a wide range of possible directions for future research.
The adenosine A1 receptor has been found to be ubiquitous throughout the entire body. This receptor has an inhibitory function on most of the tissues. In the brain, it slows metabolic activity by a combination of actions. Presynaptically, it reduces synaptic vesicle release while post synaptically it has been found to stabilize the magnesium on the NMDA receptor. Specific A1 antagonists include 8-Cyclopentyl-1,3-dipropylxanthine, Cyclopentyltheophylline or 8-cyclopentyl-1,3-dipropylxanthine, while specific agonists include 2-chloro-N-cyclopentyladenosine. Tecadenoson is an effective A1 adenosine agonist; the A1, together with A2A receptors of endogenous adenosine play a role in regulating myocardial oxygen consumption and coronary blood flow. Stimulation of the A1 receptor has a myocardial depressant effect by decreasing the conduction of electrical impulses and suppressing pacemaker cell function, resulting in a decrease in heart rate; this makes adenosine a useful medication for treating and diagnosing tachyarrhythmias, or excessively fast heart rates.
This effect on the A1 receptor explains why there is a brief moment of cardiac standstill when adenosine is administered as a rapid IV push during cardiac resuscitation. The rapid infusion causes a momentary myocardial stunning effect. In normal physiological states, this serves as a protective mechanism. However, in altered cardiac function, such as hypoperfusion caused by hypotension, heart attack or cardiac arrest caused by nonperfusing bradycardias, adenosine has a negative effect on physiological functioning by preventing necessary compensatory increases in heart rate and blood pressure that attempt to maintain cerebral perfusion. Adenosine antagonists are used in neonatal medicine. Theophylline and caffeine are nonselective adenosine antagonists that are used to stimulate respiration in premature infants. Adenosine receptors play a key role in the homeostasis of bone; the A1 receptor has been shown to stimulate osteoclast function. Studies have found that blockade of the A1 Receptor suppresses the osteoclast function, leading to increased bone density.
As with the A1, the A2A receptors are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow. The activity of A2A adenosine receptor, a G-protein coupled receptor family member, is mediated by G proteins that activate adenylyl cyclase, it is abundant in basal ganglia and platelets and it is a major target of caffeine. The A2A receptor is responsible for regulating myocardial blood flow by vasodilating the coronary arteries, which increases blood flow to the myocardium, but may lead to hypotension. Just as in A1 receptors, this serves as a protective mechanism, but may be destructive in altered cardiac function. Specific antagonists include istradefylline and SCH-58261, while specific agonists include CGS-21680 and ATL-146e; the role of A2A receptor opposes that of A1 in that it inhibits osteoclast differentiation and activates osteoblasts. Studies have shown it to be effective in decreasing inflammatory osteolysis in inflamed bone; this role could potentiate new therapeutic treatment in
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
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
Nicotiana glauca is a species of wild tobacco known by the common name tree tobacco. Its leaves are attached to the stalk by petioles, its leaves and stems are neither pubescent nor sticky like Nicotiana tabacum, it differs in the form of leaves and fusion of the outer floral parts. It grows to heights of more than two meters. Tree tobacco is native to South America but it is now widespread as an introduced species on other continents, it is a common roadside weed in the southwestern United States, an invasive plant species in California native plant habitats. The plant is smoked by Native American groups; the Cahuilla people used leaves interchangeably with other tobacco species in hunting rituals and as a poultice to treat swellings, cuts, boils, inflamed throat, swollen glands. It contains the toxic alkaloid anabasine and ingestion of the leaves can be fatal, it is being investigated for use as a biofuel. Jepson Manual Treatment Nicotiana%20glauca http://www.pfaf.org/user/Plant.aspx? LatinName=Nicotiana+glauca Plants For A Future: Nicotiana glauca Photo gallery
Theobromine known as xantheose, is a bitter alkaloid of the cacao plant, with the chemical formula C7H8N4O2. It is found in chocolate, as well as in a number of other foods, including the leaves of the tea plant, the kola nut, it is classified as others of which include theophylline and caffeine. The compounds differ. Despite its name, the compound contains no bromine—theobromine is derived from Theobroma, the name of the genus of the cacao tree with the suffix -ine given to alkaloids and other basic nitrogen-containing compounds. Theobromine is a water-soluble, bitter powder. Theobromine is white or colourless, it has an effect similar to, but lesser than, that of caffeine in the human nervous system, making it a lesser homologue. Theobromine is an isomer of theophylline, as well as paraxanthine. Theobromine is categorized as a dimethyl xanthine. Theobromine was first discovered in 1841 in cacao beans by Russian chemist Aleksandr Voskresensky. Synthesis of theobromine from xanthine was first reported in 1882 by Hermann Emil Fischer.
Theobromine is the primary alkaloid found in chocolate. Cocoa powder can vary in the amount of theobromine, from 2% theobromine, up to higher levels around 10%. Cocoa butter only contains trace amounts of theobromine. There are higher concentrations in dark than in milk chocolate. Theobromine can be found in small amounts in the kola nut, the guarana berry, yerba mate, the tea plant. 28 grams of milk chocolate contains 60 milligrams of theobromine, while the same amount of dark chocolate contains about 200 milligrams. Cocoa beans contain 1% theobromine. Plant species and components with substantial amounts of theobromine are: Theobroma cacao – seed and seed coat Theobroma bicolor – seed coat Ilex paraguariensis – leaf Camellia sinensis – leafThe mean theobromine concentrations in cocoa and carob products are: Theobromine is a purine alkaloid derived from xanthosine, a nucleoside. Cleavage of the ribose and N-methylation yields 7-methylxanthosine. 7-Methylxanthosine in turn is the precursor to theobromine, which in turn is the precursor to caffeine.
Without dietary intake, theobromine may occur in the body as it is a product of the human metabolism of caffeine, metabolised in the liver into 12% theobromine, 4% theophylline, 84% paraxanthine. In the liver, theobromine is subsequently into methyluric acid. Important enzymes include CYP1A2 and CYP2E1. Like other methylated xanthine derivatives, theobromine is both a: competitive nonselective phosphodiesterase inhibitor, which raises intracellular cAMP, activates PKA, inhibits TNF-alpha and leukotriene synthesis, reduces inflammation and innate immunity and nonselective adenosine receptor antagonist; as a phosphodiesterase inhibitor, theobromine prevents the phosphodiesterase enzymes from converting the active cAMP to an inactive form. CAMP works as a second messenger in many hormone- and neurotransmitter-controlled metabolic systems, such as the breakdown of glycogen; when the inactivation of cAMP is inhibited by a compound such as theobromine, the effects of the neurotransmitter or hormone that stimulated the production of cAMP are much longer-lived.
In general, the net result is a stimulatory effect. Theobromine is a vasodilator, a diuretic, heart stimulant, it is not used as a medicinal drug. The amount of theobromine found in chocolate is small enough that chocolate can, in general, be safely consumed by humans. At doses of 0.8–1.5 g/day, sweating and severe headaches were noted, with limited mood effects found at 250 mg/day. Theobromine and caffeine are similar in. Theobromine is weaker in both its inhibition of cyclic nucleotide phosphodiesterases and its antagonism of adenosine receptors; the potential inhibitory effect of theobromine on phosphodiesterases is seen only at amounts much higher than what people would consume in a typical diet including chocolate. Animals that metabolize theobromine more such as dogs, can succumb to theobromine poisoning from as little as 50 grams of milk chocolate for a smaller dog and 400 grams, or around nine 44-gram small milk chocolate bars, for an average-sized dog; the concentration of theobromine in dark chocolates is up to 10 times that of milk chocolate – meaning dark chocolate is far more toxic to dogs per unit weight or volume than milk chocolate.
The same risk is reported for cats as well, although cats are less to ingest sweet food, with most cats having no sweet taste receptors. Complications include digestive issues, excitability, a slow heart rate. Stages of theobromine poisoning include epileptic-like seizures and death. If caught early on, theobromine poisoning is treatable. Although not common, the effects of theobromine poisoning can be fatal. In 2014, four American black bears were found dead at a bait site in New Hampshire. A necropsy and toxicology report performed at the University of New Hampshire in 2015 confirmed they died of heart failure caused by theobromine after they consumed 41 kilograms of chocolate and doughnuts placed at the site as bait. A similar incident killed a black bear cub in Michigan in 2011; the toxicity for birds is not known, but it is assumed that it is toxic to birds. History of chocolate Theodrenaline