Riksdag
The Riksdag is the national legislature and the supreme decision-making body of Sweden. Since 1971, the Riksdag has been a unicameral legislature with 349 members, elected proportionally and serving, from 1994 onwards, on fixed four-year terms; the constitutional functions of the Riksdag are enumerated in the Instrument of Government, its internal workings are specified in greater detail in the Riksdag Act. The seat of the Riksdag is at Parliament House, on the island of Helgeandsholmen in the central parts of Stockholm; the Riksdag has its institutional roots in the feudal Riksdag of the Estates, by tradition thought to have first assembled in Arboga in 1435, in 1866 following reforms of the 1809 Instrument of Government that body was transformed into a bicameral legislature with an upper chamber and a lower chamber. The most recent general election was held on 9 September 2018; the Swedish word riksdag, in definite form riksdagen, is a general term for "parliament" or "assembly", but it is only used for Sweden's legislature and certain related institutions.
In addition to Sweden's parliament, it is used for the Parliament of Finland and the Estonian Riigikogu, as well as the historical German Reichstag and the Danish Rigsdagen. In Swedish use, riksdagen is uncapitalized. Riksdag derives from the genitive of rike, referring to royal power, dag, meaning diet or conference; the Oxford English Dictionary traces English use of the term "Riksdag" in reference to the Swedish assembly back to 1855. The roots of the modern Riksdag can be found in a 1435 meeting of the Swedish nobility in the city of Arboga; this informal organization was modified in 1527 by the first modern Swedish king Gustav I Vasa to include representatives from all the four social estates: the nobility, the clergy, the burghers, the yeomanry. This form of Ständestaat representation lasted until 1865, when representation by estate was abolished and the modern bicameral parliament established. However, it did not become a parliament in the modern sense until parliamentary principles were established in the political system in Sweden, in 1917.
On 22 June 1866, the Riksdag decided to reconstitute itself as a bicameral legislature, consisting of Första kammaren or the First Chamber, with 155 members and Andra kammaren or the Second Chamber with 233 members. The First Chamber was indirectly elected by county and city councillors, while the Second Chamber was directly elected by universal suffrage; this reform was a result of great malcontent with the old Estates, following the changes brought by the beginnings of the industrial revolution, was no longer able to provide representation for large segments of the population. By an amendment to the 1809 Instrument of Government, the general election of 1970 was the first to a unicameral assembly with 350 seats; the following general election to the unicameral Riksdag in 1973 only gave the Government the support of 175 members, while the opposition could mobilize an equal force of 175 members. In a number of cases a tied vote ensued, the final decision had to be determined by lot. To avoid any reccurrence of this unstable situation, the number of seats in the Riksdag was reduced to 349, from 1976 onwards.
The Riksdag performs the normal functions of a legislature in a parliamentary democracy. It amends the constitution and appoints a government. In most parliamentary democracies, the head of state commissions a politician to form a government. Under the new Instrument of Government enacted in 1974, that task was removed from the Monarch of Sweden and given to the Speaker of the Riksdag. To make changes to the Constitution under the new Instrument of Government, amendments must be approved twice, in two successive electoral periods with a regular general election held in between. There are 15 parliamentary committees in the Riksdag; as of February 2013, 44.7 percent of the members of the Riksdag are women. This is the world's fourth highest proportion of females in a national legislature—behind only the Parliaments of Rwanda and Cuba – hence the second-highest in the developed world and among parliamentary democracies. Following the 2014 elections, in which the share of Liberal female members of parliament plunged and the Sweden Democrats more than doubled their seats, the figure dropped to 43,5%.
Only the Left Party has a majority of female MPs. Members of the Riksdag are full-time legislators with a salary of 66 900 SEK per month. According to a survey investigation by the sociologist Jenny Hansson, Members of the Riksdag have an average work week of 66 hours, including side responsibilities. Hansson's investigation further reports; the presidium consists of three deputy speakers. They are elected for a 4-year term. After holding talks with leaders of the various party groups in the Riksdag, the speaker of the Riksdag nominates a Prime Minister; the nomination is put to a vote. The nomination is rejected only if an absolute majority of the members vote "no"; this means the Riksdag can consent to a Prime Min
Colorado River toad
The Colorado River toad known as the Sonoran Desert toad, is found in northern Mexico and the southwestern United States. Its toxin, as an exudate of glands within the skin, contains bufotenin; the Colorado River toad can grow to about 190 millimetres long and is the largest toad in the United States apart from the non-native cane toad. It is olive green or mottled brown in color. Just behind the large golden eye with horizontal pupil is a bulging kidney-shaped parotoid gland. Below this is a large circular pale green area, the tympanum or ear drum. By the corner of the mouth there is a white wart and there are white glands on the legs. All these glands produce toxic secretions. Dogs that have attacked toads have been paralyzed or killed. Raccoons have learned to pull a toad away from a pond by the back leg, turn it on its back and start feeding on its belly, a strategy that keeps the raccoon well away from the poison glands. Unlike other vertebrates, this amphibian obtains water by osmotic absorption across its abdomen.
Toads in the family bufonidae have a region of skin known as "the seat patch", which extends from mid abdomen to the hind legs and is specialized for rapid rehydration. Most of the rehydration is done through absorption of water from wet objects; the Colorado River toad is found in the lower Colorado River and the Gila River catchment areas, in southeastern California, New Mexico and much of southern Arizona. It lives in semi-arid areas throughout its range, it is semiaquatic and is found in streams, near springs, in canals and drainage ditches, under water troughs. The Colorado River toad is known to breed in artificial water bodies and as a result, the distributions and breeding habitats of these species may have been altered in south central Arizona, it makes its home in rodent burrows and is nocturnal. Its call is described as, “a weak, low-pitched toot, lasting less than a second.” Colorado River toad is sympatric with the spadefoot toad, Great Plains toad, red-spotted toad, Woodhouse's toad.
Like many other toads, they are active foragers and feed on invertebrates, small mammals, amphibians. The most active season for toads is May–September, due to greater rainfalls; the age of I. alvarius ranges from 2 to 4 years within a population at Adobe Dam in Maricopa County, Arizona. The taxonomic affinities of I. alvarius remain unclear, but immunologically, it is close to the boreas and valliceps groups. The breeding season starts in May, when the rainy season begins, can last up to August. 1–3 days after the rain is when toads begin to lay eggs in ponds, slow-moving streams, temporary pools or man-made structures that hold water. Eggs are 1.6 mm in diameter, 5–7 cm apart, encased in a long single tube of jelly with a loose but distinct outline. The female toad can lay up to 8,000 eggs; the toad's primary defense system are glands that produce a poison that may be potent enough to kill a grown dog. These parotoid glands produce the 5-MeO-DMT and Bufotenin. A single deep inhalation of the venom produces strong psychoactive effect within 15 seconds.
After inhalation, the user experiences a warm sensation and strong visual and auditory hallucinations, due to 5-MeO-DMT's high affinity for the 5-HT2 and 5-HT1A subtypes.. The toads received national attention after a story was published in the New York Times Magazine in 1994 about a California teacher who became the first person to be arrested for possessing the venom of the toads; the substance concerned, had been outlawed in California in 1970. In November 2007, a man in Kansas City, Missouri was discovered with an I. alvarius toad in his possession, charged with possession of a controlled substance after they determined he intended to use its secretions for recreational purposes. In Arizona, one may bag up to 10 toads with a fishing license, but it could constitute a criminal violation if it can be shown that one is in possession of this toad with the intent to smoke its venom. None of the states in which I. alvarius is indigenous – California and New Mexico – allows a person to remove the toad from the state.
For example, the Arizona Game and Fish Department is clear about the law in Arizona: "An individual shall not... export any live wildlife from the state. Transport, offer for sale, sell as live bait, give away, rent, display, propagate... within the state..."In California, I. alvarius has been designated as "endangered" and possession of this toad is illegal. "It is unlawful to capture, intentionally kill or injure, purchase, sell, import or export any native reptile or amphibian, or part thereof..."In New Mexico, this toad is listed as "threatened" and, taking I. alvarius is unlawful. Pauly, G. B. D. M. Hillis, D. C. Cannatella; the history of a Nearctic colonization: Molecular phylogenetics and biogeography of the Nearctic toads. Evolution 58: 2517–2535. Frost, Darrel R.. B..
Seed
A seed is an embryonic plant enclosed in a protective outer covering. The formation of the seed is part of the process of reproduction in seed plants, the spermatophytes, including the gymnosperm and angiosperm plants. Seeds are the product of the ripened ovule, after fertilization by pollen and some growth within the mother plant; the embryo is developed from the seed coat from the integuments of the ovule. Seeds have been an important development in the reproduction and success of gymnosperm and angiosperm plants, relative to more primitive plants such as ferns and liverworts, which do not have seeds and use water-dependent means to propagate themselves. Seed plants now dominate biological niches on land, from forests to grasslands both in hot and cold climates; the term "seed" has a general meaning that antedates the above – anything that can be sown, e.g. "seed" potatoes, "seeds" of corn or sunflower "seeds". In the case of sunflower and corn "seeds", what is sown is the seed enclosed in a shell or husk, whereas the potato is a tuber.
Many structures referred to as "seeds" are dry fruits. Plants producing berries are called baccate. Sunflower seeds are sometimes sold commercially while still enclosed within the hard wall of the fruit, which must be split open to reach the seed. Different groups of plants have other modifications, the so-called stone fruits have a hardened fruit layer fused to and surrounding the actual seed. Nuts are the one-seeded, hard-shelled fruit of some plants with an indehiscent seed, such as an acorn or hazelnut. Seeds are produced in several related groups of plants, their manner of production distinguishes the angiosperms from the gymnosperms. Angiosperm seeds are produced in a hard or fleshy structure called a fruit that encloses the seeds for protection in order to secure healthy growth; some fruits have layers of both fleshy material. In gymnosperms, no special structure develops to enclose the seeds, which begin their development "naked" on the bracts of cones. However, the seeds do become covered by the cone scales.
Seed production in natural plant populations varies from year to year in response to weather variables and diseases, internal cycles within the plants themselves. Over a 20-year period, for example, forests composed of loblolly pine and shortleaf pine produced from 0 to nearly 5 million sound pine seeds per hectare. Over this period, there were six bumper, five poor, nine good seed crops, when evaluated for production of adequate seedlings for natural forest reproduction. Angiosperm seeds consist of three genetically distinct constituents: the embryo formed from the zygote, the endosperm, triploid, the seed coat from tissue derived from the maternal tissue of the ovule. In angiosperms, the process of seed development begins with double fertilization, which involves the fusion of two male gametes with the egg cell and the central cell to form the primary endosperm and the zygote. Right after fertilization, the zygote is inactive, but the primary endosperm divides to form the endosperm tissue.
This tissue becomes the food the young plant will consume until the roots have developed after germination. After fertilization the ovules develop into the seeds; the ovule consists of a number of components: The funicle or seed stalk which attaches the ovule to the placenta and hence ovary or fruit wall, at the pericarp. The nucellus, the remnant of the megasporangium and main region of the ovule where the megagametophyte develops; the micropyle, a small pore or opening in the apex of the integument of the ovule where the pollen tube enters during the process of fertilization. The chalaza, the base of the ovule opposite the micropyle, where integument and nucellus are joined together; the shape of the ovules as they develop affects the final shape of the seeds. Plants produce ovules of four shapes: the most common shape is called anatropous, with a curved shape. Orthotropous ovules are straight with all the parts of the ovule lined up in a long row producing an uncurved seed. Campylotropous ovules have a curved megagametophyte giving the seed a tight "C" shape.
The last ovule shape is called amphitropous, where the ovule is inverted and turned back 90 degrees on its stalk. In the majority of flowering plants, the zygote's first division is transversely oriented in regards to the long axis, this establishes the polarity of the embryo; the upper or chalazal pole becomes the main area of growth of the embryo, while the lower or micropylar pole produces the stalk-like suspensor that attaches to the micropyle. The suspensor absorbs and manufactures nutrients from the endosperm that are used during the embryo's growth; the main components of the embryo are: The cotyledons, the seed leaves, attached to the embryonic axis. There may be two; the cotyledons are the source of nutrients in the non-endospermic dicotyledons, in which case they replace the endosperm, are thick and leathery. In endospermic seeds the cotyledons are papery. Dicotyledons have the point of attachment opposite one another on the axis; the epicotyl, the embryonic axis above the point of attachment of the cotyledon.
The plumule, the tip of the epicotyl, has a feathery appearance due to the presence of young leaf primordia at the apex, will become the shoot upon germination. The hypocotyl, the embryonic axis below the point of attachment of the cotyledon, connecting the epicotyl and the radicle, being the stem-root transition zone; the radicle, the basal tip of the hy
Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, poison, or other substance is taken into the body. Routes of administration are classified by the location at which the substance is applied. Common examples include intravenous administration. Routes can be classified based on where the target of action is. Action may be enteral, or parenteral. Route of administration and dosage form are aspects of drug delivery. Routes of administration are classified by application location; the route or course the active substance takes from application location to the location where it has its target effect is rather a matter of pharmacokinetics. Exceptions include the transdermal or transmucosal routes, which are still referred to as routes of administration; the location of the target effect of active substances are rather a matter of pharmacodynamics. An exception is topical administration, which means that both the application location and the effect thereof is local. Topical administration is sometimes defined as both a local application location and local pharmacodynamic effect, sometimes as a local application location regardless of location of the effects.
Administration through the gastrointestinal tract is sometimes termed enteral or enteric administration. Enteral/enteric administration includes oral and rectal administration, in the sense that these are taken up by the intestines. However, uptake of drugs administered orally may occur in the stomach, as such gastrointestinal may be a more fitting term for this route of administration. Furthermore, some application locations classified as enteral, such as sublingual and sublabial or buccal, are taken up in the proximal part of the gastrointestinal tract without reaching the intestines. Enteral administration can be used for systemic administration, as well as local, such as in a contrast enema, whereby contrast media is infused into the intestines for imaging. However, for the purposes of classification based on location of effects, the term enteral is reserved for substances with systemic effects. Many drugs as tablets, capsules, or drops are taken orally. Administration methods directly into the stomach include those by gastric feeding tube or gastrostomy.
Substances may be placed into the small intestines, as with a duodenal feeding tube and enteral nutrition. Enteric coated tablets are designed to dissolve in the intestine, not the stomach, because the drug present in the tablet causes irritation in the stomach; the rectal route is an effective route of administration for many medications those used at the end of life. The walls of the rectum absorb many medications and effectively. Medications delivered to the distal one-third of the rectum at least avoid the "first pass effect" through the liver, which allows for greater bio-availability of many medications than that of the oral route. Rectal mucosa is vascularized tissue that allows for rapid and effective absorption of medications. A suppository is a solid dosage form. In hospice care, a specialized rectal catheter, designed to provide comfortable and discreet administration of ongoing medications provides a practical way to deliver and retain liquid formulations in the distal rectum, giving health practitioners a way to leverage the established benefits of rectal administration.
The parenteral route is any route, not enteral. Parenteral administration can be performed by injection, that is, using a needle and a syringe, or by the insertion of an indwelling catheter. Locations of application of parenteral administration include: central nervous systemepidural, e.g. epidural anesthesia intracerebral direct injection into the brain. Used in experimental research of chemicals and as a treatment for malignancies of the brain; the intracerebral route can interrupt the blood brain barrier from holding up against subsequent routes. Intracerebroventricular administration into the ventricular system of the brain. One use is as a last line of opioid treatment for terminal cancer patients with intractable cancer pain. Epicutaneous, it can be used both for local effect as in allergy testing and typical local anesthesia, as well as systemic effects when the active substance diffuses through skin in a transdermal route. Sublingual and buccal medication administration is a way of giving someone medicine orally.
Sublingual administration is. The word "sublingual" means "under the tongue." Buccal administration involves placement of the drug between the cheek. These medications can come in the form of films, or sprays. Many drugs are designed for sublingual administration, including cardiovascular drugs, barbiturates, opioid analgesics with poor gastrointestinal bioavailability and vitamins and minerals. Extra-amniotic administration, between the endometrium and fetal membranes nasal administration (th
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
Metabolism
Metabolism is the set of life-sustaining chemical reactions in organisms. The three main purposes of metabolism are: the conversion of food to energy to run cellular processes; these enzyme-catalyzed reactions allow organisms to grow and reproduce, maintain their structures, respond to their environments.. Metabolic reactions may be categorized as catabolic - the breaking down of compounds. Catabolism releases energy, anabolism consumes energy; the chemical reactions of metabolism are organized into metabolic pathways, in which one chemical is transformed through a series of steps into another chemical, each step being facilitated by a specific enzyme. Enzymes are crucial to metabolism because they allow organisms to drive desirable reactions that require energy that will not occur by themselves, by coupling them to spontaneous reactions that release energy. Enzymes act as catalysts - they allow a reaction to proceed more - and they allow the regulation of the rate of a metabolic reaction, for example in response to changes in the cell's environment or to signals from other cells.
The metabolic system of a particular organism determines which substances it will find nutritious and which poisonous. For example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals; the basal metabolic rate of an organism is the measure of the amount of energy consumed by all of these chemical reactions. A striking feature of metabolism is the similarity of the basic metabolic pathways among vastly different species. For example, the set of carboxylic acids that are best known as the intermediates in the citric acid cycle are present in all known organisms, being found in species as diverse as the unicellular bacterium Escherichia coli and huge multicellular organisms like elephants; these similarities in metabolic pathways are due to their early appearance in evolutionary history, their retention because of their efficacy. Most of the structures that make up animals and microbes are made from three basic classes of molecule: amino acids and lipids; as these molecules are vital for life, metabolic reactions either focus on making these molecules during the construction of cells and tissues, or by breaking them down and using them as a source of energy, by their digestion.
These biochemicals can be joined together to make polymers such as DNA and proteins, essential macromolecules of life. Proteins are made of amino acids arranged in a linear chain joined together by peptide bonds. Many proteins are enzymes. Other proteins have structural or mechanical functions, such as those that form the cytoskeleton, a system of scaffolding that maintains the cell shape. Proteins are important in cell signaling, immune responses, cell adhesion, active transport across membranes, the cell cycle. Amino acids contribute to cellular energy metabolism by providing a carbon source for entry into the citric acid cycle when a primary source of energy, such as glucose, is scarce, or when cells undergo metabolic stress. Lipids are the most diverse group of biochemicals, their main structural uses are as part of biological membranes both internal and external, such as the cell membrane, or as a source of energy. Lipids are defined as hydrophobic or amphipathic biological molecules but will dissolve in organic solvents such as benzene or chloroform.
The fats are a large group of compounds that contain fatty glycerol. Several variations on this basic structure exist, including alternate backbones such as sphingosine in the sphingolipids, hydrophilic groups such as phosphate as in phospholipids. Steroids such as cholesterol are another major class of lipids. Carbohydrates are aldehydes or ketones, with many hydroxyl groups attached, that can exist as straight chains or rings. Carbohydrates are the most abundant biological molecules, fill numerous roles, such as the storage and transport of energy and structural components; the basic carbohydrate units are called monosaccharides and include galactose and most glucose. Monosaccharides can be linked together to form polysaccharides in limitless ways; the two nucleic acids, DNA and RNA, are polymers of nucleotides. Each nucleotide is composed of a phosphate attached to a ribose or deoxyribose sugar group, attached to a nitrogenous base. Nucleic acids are critical for the storage and use of genetic information, its interpretation through the processes of transcription and protein biosynthesis.
This information is propagated through DNA replication. Many viruses have an RNA genome, such as HIV, which uses reverse transcription to create a DNA template from its viral RNA genome. RNA in ribozymes such as spliceosomes and ribosomes is similar to enzymes as it can catalyze chemical reactions. Individual nucleosides are made
Reuptake
Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal or glial cell after it has performed its function of transmitting a neural impulse. Reuptake is necessary for normal synaptic physiology because it allows for the recycling of neurotransmitters and regulates the level of neurotransmitter present in the synapse, thereby controlling how long a signal resulting from neurotransmitter release lasts; because neurotransmitters are too large and hydrophilic to diffuse through the membrane, specific transport proteins are necessary for the reabsorption of neurotransmitters. Much research, both biochemical and structural, has been performed to obtain clues about the mechanism of reuptake; the first primary sequence of a reuptake protein was published in 1990. The technique for protein sequence determination relied upon the purification and cloning of the transporter protein in question, or expression cloning strategies in which transport function was used as an assay for cDNA species coding for that transporter.
After separation, it was realized. Further exploration in the field of reuptake proteins found that many of the transporters associated with important neurotransmitters within the body were very similar in sequence to the GABA and norepinephrine transporters; the members of this new family include transporters for dopamine, serotonin, proline and GABA. They were called Na+/Cl− dependent neurotransmitter transporters. Sodium and chloride ion dependence will be discussed in the mechanism of action. Using the commonalities among sequences and hydropathy plot analyses, it was predicted that there are 12 hydrophobic membrane spanning regions in the ‘Classical’ transporter family. In addition to this, the N- and C-termini exist in the intracellular space; these proteins all have an extended extracellular loop between the third and fourth transmembrane sequences. Site-directed chemical labeling experiments verified the predicted topological organization of the serotonin transporter. In addition to neurotransmitter transporters, many other proteins in both animals and prokaryotes were found with similar sequences, indicating a larger family of Neurotransmitter:Sodium Symporters.
One of these proteins, LeuT, from Aquifex aeolicus, was crystallized by Yamashita et al. with high resolution, revealing a molecule of leucine and two Na+ ions bound near the center of the protein. They found that the transmembrane helices 1 and 6 contained unwound segments in the middle of the membrane. Along with these two helices, TM helices 3 and 8 and the areas surrounding the unwound sections of 1 and 6 formed the substrate and sodium ion binding sites; the crystal structure revealed pseudo-symmetry in LeuT, in which the structure of TM helices 1-5 is reflected in the structure of helices 6-10. There is an extracellular cavity in the protein, into which protrudes a helical hairpin formed by extracellular loop EL4. In TM1, an aspartate distinguishes monoamine NSS transporters from amino acid transporters which contain a glycine at the same position. External and internal “gates” were assigned to pairs of negatively and positively charged residues in the extracellular cavity and near the cytoplasmic ends of TM helices 1 and 8.
The classic transporter proteins use transmembrane ion gradients and electrical potential to transport neurotransmitter across the membrane of the presynaptic neuron. Typical neurotransmitter sodium symport transporters, which are Na+ and Cl− ion dependent, take advantage of both Na+ and Cl− gradients, inwardly directed across the membrane; the ions flow down their concentration gradients, in many cases leading to transmembrane charge movement, enhanced by the membrane potential. These forces pull the neurotransmitter substrate into the cell against its own concentration gradient. At a molecular level, Na+ ions stabilize amino acid binding at the substrate site and hold the transporter in an outward-open conformation that allows substrate binding; the role of the Cl− ion in the symport mechanism has been proposed to be for stabilizing the charge of the symported Na+. After ion and substrate binding have taken place, some conformational change must occur. From the conformational differences between the structure of TMs 1-5 and that of TMs 6-10, from the identification of a substrate permeation pathway between the binding site of SERT and the cytoplasm, a mechanism for conformational change was proposed in which a four-helix bundle composed of TMs 1, 2, 6 and 7 changes its orientation within the rest of the protein.
A structure of LeuT in the inward-open conformation subsequently demonstrated that the major component of the conformational change represents movement of the bundle relative to the rest of the protein. The main objective of a reuptake inhibitor is to decrease the rate by which neurotransmitters are reabsorbed into the presynaptic neuron, increasing the concentration of neurotransmitter in the synapse; this increases neurotransmitter binding to pre- and postsynaptic neurotransmitter receptors. Depending on the neuronal system in question, a reuptake inhibitor can have drastic effects on cognition and behavior. Non-competitive inhibition of the bacterial homologue LeuT by tricyclic antidepressants resulted from binding of these inhibitors in the extracellular permeation pathway. However, the competitive nature of serotonin transport inhibition by antidepressants suggests that in neurotransmitter transporters, they bind in a site overlapping the substrate site. Horschitz et al. examined reuptake inhibitor selectivity among the rat serotonin reuptake protein expressed in human em
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