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76-412: The vesicular monoamine transporter (VMAT) is a transport protein integrated into the membranes of synaptic vesicles of presynaptic neurons . It transports monoamine neurotransmitters – such as dopamine , serotonin , norepinephrine , epinephrine , and histamine – into the vesicles , which release the neurotransmitters into synapses, as chemical messages to postsynaptic neurons. VMATs utilize

152-410: A light microscope except as points where the membranes of two cells appear to touch, but their cellular elements can be visualized clearly using an electron microscope . Chemical synapses pass information directionally from a presynaptic cell to a postsynaptic cell and are therefore asymmetric in structure and function. The presynaptic axon terminal , or synaptic bouton, is a specialized area within

228-735: A locus 8p21.3 that has been strongly connected to schizophrenia susceptibility. Over-expression of VMAT2 results in increased secretion of neurotransmitter upon cell stimulation. Data suggests that deletion of the VMAT2 genes does not affect the size of small clear-core vesicles. VMATs may be regulated by changes in transcription , post-transcriptional modifications such as phosphorylation and mRNA splicing of exons , and vesicular transport inactivation facilitated by heterotrimeric G-proteins , which are thought to be possessed by chromaffin granules, and have shown to regulate small clear-core vesicles. Specific heterotrimeric G-protein type regulation

304-408: A proton gradient generated by V-ATPases in vesicle membranes to power monoamine import. Pharmaceutical drugs that target VMATs have possible applications for many conditions, leading to a plethora of biological research, including hypertension , drug addiction , psychiatric disorders, Parkinson's disease , and other neurological disorders. Many drugs that target VMATs act as inhibitors and alter

380-407: A 'quantum'), and n , the number of release sites. "Unitary connection" usually refers to an unknown number of individual synapses connecting a presynaptic neuron to a postsynaptic neuron. The amplitude of postsynaptic potentials (PSPs) can be as low as 0.4 mV to as high as 20 mV. The amplitude of a PSP can be modulated by neuromodulators or can change as a result of previous activity. Changes in

456-421: A decrease in the efficacy of the synapse, called depression, or an increase in efficacy, called potentiation. These changes can either be long-term or short-term. Forms of short-term plasticity include synaptic fatigue or depression and synaptic augmentation . Forms of long-term plasticity include long-term depression and long-term potentiation . Synaptic plasticity can be either homosynaptic (occurring at

532-563: A dendrite. In some fish and amphibians , electrical synapses can be found within the same terminal of a chemical synapse, as in Mauthner cells . One of the most important features of chemical synapses is that they are the site of action for the majority of psychoactive drugs . Synapses are affected by drugs, such as curare, strychnine, cocaine, morphine, alcohol, LSD, and countless others. These drugs have different effects on synaptic function, and often are restricted to synapses that use

608-520: A different binding site from the RES/substrate binding site, or to a different conformation of the RES/substrate binding site. This site is believed to be located at the N-terminus , based on studies done in bovine VMAT2. Tyr434 and asp461 are identified as being responsible for the high-affinity interaction of TBZ, serotonin, and histamine in VMAT2. Unlike methamphetamine, amphetamine binds to

684-466: A few days of birth. More specifically, inhibition of VMAT2 may cause an increase in cytosolic catecholamine levels, which can result in an increase in efflux of catecholamines through the cell membrane , depleting catecholamine concentrations and causing increased oxidative stress and oxidative damage to the neuron. Heterozygous VMAT mutants display hypersensitivity to amphetamine , cocaine, and MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine),

760-425: A high-affinity amine-binding site in the cytosolic phase, and the second H efflux is coupled with a second large conformational change that leads to amine transport from the cytosolic side into the vesicle, reducing amine-binding affinity. Studies indicate that the amino acid residue His419, located on the domain between TMDs X and XI of rat VMAT1, plays a role in energy coupling to the amine transport by assisting

836-436: A large energy source to store large quantities of neurotransmitters into a small vesicular space at high concentrations. VMAT transport relies on the pH and electrochemical gradient generated by a vesicular H-ATPase . The current model of VMAT function proposes that the efflux of two protons (H) against the H gradient is coupled with influx of one monoamine. The first H efflux generates a transporter conformation associated with

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912-409: A neurotransmitter is released at a synapse, it reaches its highest concentration inside the narrow space of the synaptic cleft, but some of it is certain to diffuse away before being reabsorbed or broken down. If it diffuses away, it has the potential to activate receptors that are located either at other synapses or on the membrane away from any synapse. The extrasynaptic activity of a neurotransmitter

988-449: A prominent postsynaptic density. Symmetric synapses are typically inhibitory. The synaptic cleft —also called synaptic gap —is a gap between the pre- and postsynaptic cells that is about 20 nm (0.02 μ) wide. The small volume of the cleft allows neurotransmitter concentration to be raised and lowered rapidly. An autapse is a chemical (or electrical) synapse formed when the axon of one neuron synapses with its own dendrites. Here

1064-407: A receptor molecule, it must be removed to allow for the postsynaptic membrane to continue to relay subsequent EPSPs and/or IPSPs . This removal can happen through one or more processes: The strength of a synapse has been defined by Bernard Katz as the product of (presynaptic) release probability pr , quantal size q (the postsynaptic response to the release of a single neurotransmitter vesicle,

1140-435: A set of proteins in the presynaptic terminal known as SNAREs . As a whole, the protein complex or structure that mediates the docking and fusion of presynaptic vesicles is called the active zone. The membrane added by the fusion process is later retrieved by endocytosis and recycled for the formation of fresh neurotransmitter-filled vesicles. An exception to the general trend of neurotransmitter release by vesicular fusion

1216-407: A single synapse) or heterosynaptic (occurring at multiple synapses). Homosynaptic plasticity (or also homotropic modulation) is a change in the synaptic strength that results from the history of activity at a particular synapse. This can result from changes in presynaptic calcium as well as feedback onto presynaptic receptors, i.e. a form of autocrine signaling . Homosynaptic plasticity can affect

1292-639: A single unit to help sort VMAT2 to large dense course vesicles. Acidic glutamate residues located upstream of the dileucine motif are known to be important for localization of VMAT2 to large dense core vesicles; these residues are also conserved in VMAT1. Although both VMAT1 and VMAT2 are encoded by two different genes , the individual genetic sequences demonstrate high homology. Polymorphisms in VMAT2 that affect regulation and quantitative expression may pose genetic risk factors for PD. A specific VMAT1 gene ( SLC18A1 ) has several associated polymorphisms , which have

1368-455: A specific neurotransmitter. For example, curare is a poison that stops acetylcholine from depolarizing the postsynaptic membrane, causing paralysis . Strychnine blocks the inhibitory effects of the neurotransmitter glycine , which causes the body to pick up and react to weaker and previously ignored stimuli, resulting in uncontrollable muscle spasms . Morphine acts on synapses that use endorphin neurotransmitters, and alcohol increases

1444-466: A synapse may in effect diminish as a train of action potentials arrive in rapid succession – a phenomenon that gives rise to the so-called frequency dependence of synapses. The nervous system exploits this property for computational purposes, and can tune its synapses through such means as phosphorylation of the proteins involved. Synaptic transmission can be changed by previous activity. These changes are called synaptic plasticity and may result in either

1520-479: Is a membrane protein that acts as such a carrier. A vesicular transport protein is a transmembrane or membrane associated protein . It regulates or facilitates the movement by vesicles of the contents of the cell. Synaptic cleft Chemical synapses are biological junctions through which neurons ' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands . Chemical synapses allow neurons to form circuits within

1596-508: Is a summary of the sequence of events that take place in synaptic transmission from a presynaptic neuron to a postsynaptic cell. Each step is explained in more detail below. Note that with the exception of the final step, the entire process may run only a few hundred microseconds, in the fastest synapses. The release of a neurotransmitter is triggered by the arrival of a nerve impulse (or action potential ) and occurs through an unusually rapid process of cellular secretion ( exocytosis ). Within

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1672-455: Is again neurons of the sympathetic nervous system , which release noradrenaline , which, in addition, generates an inhibitory effect on presynaptic terminals of neurons of the parasympathetic nervous system . In general, if an excitatory synapse is strong enough, an action potential in the presynaptic neuron will trigger an action potential in the postsynaptic cell. In many cases the excitatory postsynaptic potential (EPSP) will not reach

1748-413: Is an electrically conductive link between two abutting neurons that is formed at a narrow gap between the pre- and postsynaptic cells , known as a gap junction . At gap junctions, cells approach within about 3.5  nm of each other, rather than the 20 to 40 nm distance that separates cells at chemical synapses. As opposed to chemical synapses, the postsynaptic potential in electrical synapses

1824-408: Is estimated to contain from 10 to 5 × 10 (100–500 trillion) synapses. Every cubic millimeter of cerebral cortex contains roughly a billion ( short scale , i.e. 10 ) of them. The number of synapses in the human cerebral cortex has separately been estimated at 0.15 quadrillion (150 trillion) The word "synapse" was introduced by Sir Charles Scott Sherrington in 1897. Chemical synapses are not

1900-431: Is expressed in rat adrenal medulla cells, whereas VMAT2 is the major transporter in bovine adrenal medulla cells. VMAT1 and VMAT2 are acidic glycoproteins with a molecular weight of approximately 70 kDa . Both isoforms are transmembrane proteins with 12 transmembrane domains (TMDs). VMATs function by loading monoamines—dopamine, serotonin, histamine, norepinephrine, and epinephrine—into transport vesicles. VMATs use

1976-400: Is found in the type II receptor cells of mammalian taste buds . Here the neurotransmitter ATP is released directly from the cytoplasm into the synaptic cleft via voltage gated channels. Receptors on the opposite side of the synaptic gap bind neurotransmitter molecules. Receptors can respond in either of two general ways. First, the receptors may directly open ligand-gated ion channels in

2052-436: Is known as volume transmission . It is well established that such effects occur to some degree, but their functional importance has long been a matter of controversy. Recent work indicates that volume transmission may be the predominant mode of interaction for some special types of neurons. In the mammalian cerebral cortex, a class of neurons called neurogliaform cells can inhibit other nearby cortical neurons by releasing

2128-464: Is known to be hydrophobic , which is thought to contribute to ligand binding affinity. Methamphetamine binds to the RES site on VMATs. The current working model proposes that RES and the substrate bind to a single site in a pH-gradient modulated conformational structure of the transporter. The conformation occurs after the transport of one H across the membrane and into the vesicle; proton transport drives

2204-618: Is not caused by the opening of ion channels by chemical transmitters, but rather by direct electrical coupling between both neurons. Electrical synapses are faster than chemical synapses. Electrical synapses are found throughout the nervous system, including in the retina , the reticular nucleus of the thalamus , the neocortex , and in the hippocampus . While chemical synapses are found between both excitatory and inhibitory neurons, electrical synapses are most commonly found between smaller local inhibitory neurons. Electrical synapses can exist between two axons, two dendrites, or between an axon and

2280-408: Is present in all cell groups damaged by Parkinson's disease (PD); these findings have identified VMAT2 as a target for preventing Parkinson's. VMAT2 presence does not independently protect neurons from PD, but a decrease in VMAT2 expression has been shown to correlate with susceptibility to the disease, which may be due to a ratio between the dopamine transporter and VMAT2. Based on the understanding

2356-519: Is the basis for our current understanding of neurotransmitter release as exocytosis and for which Katz received the Nobel Prize in Physiology or Medicine in 1970. In the late 1960s, Ricardo Miledi and Katz advanced the hypothesis that depolarization-induced influx of calcium ions triggers exocytosis . Sir Charles Scott Sherringtonin coined the word 'synapse' and the history of the word

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2432-876: Is thought to bind to a different site than other monoamines. Unlike catecholamines and histamine, the indoleamine serotonin binds to VMAT1 and VMAT2 with a similar affinity for both transporter isoforms. VMAT1 has a lower turnover number and a lower affinity for most monoamine substrates than VMAT2, which may be because of VMAT2's location in the central nervous system, which demands fast recovery from neurotransmitter release in order to prepare for subsequent releases. The uptake efficiencies of each VMAT substrate can be ranked in order of efficiency as: serotonin, dopamine, epinephrine, and norepinephrine. Methamphetamines decrease V max , while cocaine increases V max reversibly in rat brain. The effects of VMAT inhibition have been studied in-depth in animal models. Mutant homozygous VMAT(-/-) mice move little, feed poorly, and die within

2508-569: Is tissue-dependent for VMAT2; it is not known whether this is the case for VMAT1. Heterotrimeric G-protein Gαo2 decreases VMAT1 activity in pancreatic and adrenal medulla cells , and activates heterotrimeric G-proteins to inhibit VMAT2 activity in the brain, regardless of whether they are localized on small clear-core or large-dense-core vesicles. The activated heterotrimeric G-protein Gαq downregulates VMAT2-mediated serotonin transport in blood platelets, but not in

2584-570: Is utilized with clonidine to perform inhibitory effects on the SNS. Heterosynaptic plasticity (or also heterotropic modulation) is a change in synaptic strength that results from the activity of other neurons. Again, the plasticity can alter the number of vesicles or their replenishment rate or the relationship between calcium and vesicle release. Additionally, it could directly affect calcium influx. Heterosynaptic plasticity can also be postsynaptic in nature, affecting receptor sensitivity. One example

2660-464: The central nervous system . They are crucial to the biological computations that underlie perception and thought . They allow the nervous system to connect to and control other systems of the body. At a chemical synapse, one neuron releases neurotransmitter molecules into a small space (the synaptic cleft ) that is adjacent to another neuron. The neurotransmitters are contained within small sacs called synaptic vesicles , and are released into

2736-445: The medulla of the adrenal glands . VMAT2 favors expression in a variety of monoaminergic cells of the central nervous system , such as the brain, sympathetic nervous system , mast cells , and cells containing histamine in the gut. It is prevalent in β-cells , expressed in blood platelets , and co-expressed in chromaffin cells. Expression of the two transporters in internal organs seems to differ between species: only VMAT1

2812-462: The protonated amino group and hydroxyl group on the catechol or indole rings. Cocaine and methylphenidate (MPD, also known as Ritalin and Concerta) are believed to interact with VMAT2 to cause a shift in VMAT2 "from a plasmalemmal membrane-associated fraction to a vesicle-enriched, nonmembrane-associated fraction." Consistent with catecholamine-binding affinity, RES has a threefold higher affinity for VMAT2 than for VMAT1. The RES binding site

2888-419: The striatum involved in clinical depression, including the nucleus accumbens shell but not the core, the ventral tegmental area , and the substantia nigra 's pars compacta . The reduced VMAT2 protein levels were not accompanied by similar levels of VMAT2 mRNA alterations. Based on these findings, it has been proposed that VMAT2 activity is not altered at the level of genetic expression, but may be altered at

2964-477: The threshold for eliciting an action potential. When action potentials from multiple presynaptic neurons fire simultaneously, or if a single presynaptic neuron fires at a high enough frequency, the EPSPs can overlap and summate. If enough EPSPs overlap, the summated EPSP can reach the threshold for initiating an action potential. This process is known as summation, and can serve as a high pass filter for neurons. On

3040-599: The 1970s, scientists like Arvid Carlsson recognized the need to understand how transport systems and ion gradients work in different organisms in order to explore new treatment options such as reserpine (RES). Researchers discovered inhibitors that blocked the uptake of neurotransmitters into vesicles, suggesting the existence of VMATs. A decade later, molecular genetic tools have improved methods for protein identification. Scientists have used these tools to analyze DNA and amino acid sequences, and discovered that transporters in bacteria and humans were very similar, which emphasized

3116-572: The RES binding site. TBZ, DTBZOH, ketanserin, and lobeline bind to the TBZ binding site. Many psychostimulants , including substituted amphetamines and cocaine, are known to interact with VMAT2. Studies indicate that both amphetamines and cocaine act to increase non-exocytotic release of dopamine in specific regions of the brain by interacting directly with VMAT2 function. VMAT is a main target of methamphetamine. Studies indicate that substituted amphetamines including methamphetamine interact with VMAT2 at

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3192-413: The TBZ site on hVMAT2. Unlike RES inhibition, TBZ inhibition is only affected by very high concentrations of monoamines; however, single injections of RES can inhibit TBZ binding. ketanserin (KET) and lobeline also bind to the TBZ binding site conformation. Three to four glycosylation sites exist in the vesicular matrix on a loop between TMD I and TMD II. In biology, the vesicle matrix refers to

3268-621: The TBZ/DTBZOH binding site. By acting as a negative allosteric modulator , methamphetamine blocks the presynaptic cell's ability to use VMAT for vesicular packaging. Methamphetamine alters the subcellular location of VMAT2, which affects the distribution of dopamine in the cell. Treatment with methamphetamine relocates VMAT2 from a vesicle-enriched fraction to a location that is not continuous with synaptosomal preparations. Repeated amphetamine exposure may increase VMAT2 mRNA in certain brain regions with little or no decline upon withdrawal from

3344-511: The VMAT trafficking cycle are believed to be encoded in the C-terminus. A dileucine motif in the C-terminus is required for VMAT2 endocytosis . Studies suggest the acidic residues in the dileucine motif sort VMAT2 away from constitutive secretory vesicles and into the regulated secretory pathway . The hydrophobic residues in the dileucine motif are thought to couple with the acidic residues as

3420-489: The axon of the presynaptic cell that contains neurotransmitters enclosed in small membrane-bound spheres called synaptic vesicles (as well as a number of other supporting structures and organelles, such as mitochondria and endoplasmic reticulum ). Synaptic vesicles are docked at the presynaptic plasma membrane at regions called active zones . Immediately opposite is a region of the postsynaptic cell containing neurotransmitter receptors ; for synapses between two neurons

3496-505: The brain, where Gαq completely inhibits VMAT2 activity. Although the exact signalling pathway for G-protein mediated regulation of VMATs is not known, it has recently been described that implicated G-proteins act directly on the VMATs. VMAT2 has been shown to contribute to many clinical neurological disorders including drug addiction, mood disorders, and stress, as well as Parkinson's disease and Alzheimer's disease. Studies indicate VMAT2 mRNA

3572-444: The drug. A study performed by Sonsalla et al. demonstrated that methamphetamine treatment decreases DHTBZ binding and vesicular dopamine uptake. Another study demonstrated that multiple high doses of methamphetamine removed DTBZ binding sites from the vesicles. In addition to an interaction with the TBZ/DTBZOH binding site, some researchers propose that substituted amphetamines like methamphetamine decrease dopamine uptake because of

3648-488: The finding that amphetamine administration correlates with decreased dopamine release from vesicles and a neurotoxic increase in intracellular dopamine. Transport protein Carrier proteins are proteins involved in the movement of ions , small molecules , or macromolecules , such as another protein, across a biological membrane . Carrier proteins are integral membrane proteins; that is, they exist within and span

3724-482: The first proton-dependent conformational change. It has been proposed that RES inhibits VMAT by interacting with this conformation. VMAT gene sequence analysis demonstrates that four aspartic acid residues in the middle region of TMDs I, VI, X, and XI and one lysine residue in TMD II have highly conserved gene sequences, suggesting these residues play a critical role in transporter structure and function. Specifically,

3800-419: The functional level in ways that may correlate with clinical depression. Many psychostimulant drugs are known to interact with VMAT, including amphetamine analogs such as methamphetamine, cocaine, and ecstasy (MDMA). VMAT inhibitors tend to fall into two classes; those that interact with the RES binding site and those that interact with the TBZ binding site. RES, methoxytetrabenazine, and amiodarone bind to

3876-545: The importance and universality of transporters. The transporters were first structurally identified by cloning VMATs in rats. The VMAT were first isolated and purified in bovine chromaffin granules, in both its native and denatured forms. There are two types of VMATs expressed in humans: VMAT1 and VMAT2 . VMAT1 is expressed mainly in large dense-core vesicles (LDCVs) of the peripheral nervous system. VMAT1 may be found in neuroendocrine cells , particularly chromaffin and enterochromaffin granules, which are primarily found in

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3952-708: The increased cytosolic dopamine levels lead to dopaminergic cell death in PD, it has been proposed that regulatory polymorphisms in VMAT2 affect VMAT2 quantitative expression, and may serve as a genetic risk factor for PD. Specifically, the SLC18A2 promoter region for the VMAT2 gene has been identified as an area where several polymorphisms form discrete haplotypes . Studies using a genetic rodent model to understand clinical depression in humans suggest that VMAT2 genetic or functional alterations may be involved in depression. Reduced VMAT2 levels were identified in specific subregions of

4028-418: The inhibitory effects of the neurotransmitter GABA . LSD interferes with synapses that use the neurotransmitter serotonin . Cocaine blocks reuptake of dopamine and therefore increases its effects. During the 1950s, Bernard Katz and Paul Fatt observed spontaneous miniature synaptic currents at the frog neuromuscular junction . Based on these observations, they developed the 'quantal hypothesis' that

4104-400: The kinetics of the protein. Much research regarding the effects of altered VMATs on biological systems is still ongoing. Monoamines transported by VMATs are mainly noradrenaline , adrenaline , dopamine , serotonin , histamine , and trace amines . Exogenous substrates include guanethidine and MPP . VMAT research began in 1958 when Nils-Åke Hillarp discovered secretory vesicles . In

4180-426: The latter being a substance causally linked to Parkinson's disease (PD) in rodents. This suggests a protective role of VMATs against oxidative stress through removal of such substances from the cytosol. VMAT inhibitors include: Two known binding sites for VMAT inhibitors include the RES binding site and the TBZ binding site. Some evidence suggests these two sites may overlap or exist as two separate conformations of

4256-406: The main dendritic shaft called dendritic spines . Synapses may be described as symmetric or asymmetric. When examined under an electron microscope, asymmetric synapses are characterized by rounded vesicles in the presynaptic cell, and a prominent postsynaptic density. Asymmetric synapses are typically excitatory. Symmetric synapses in contrast have flattened or elongated vesicles, and do not contain

4332-492: The material or tissue between cells in which more specialized structures are embedded. Two of the glycosylation sites, the N -linked glycosylation terminal and C -linked terminal , are located in the cytosolic portion of the vesicle. The highest amount of genetic variance between VMAT1 and VMAT2 exists near the N- and C- terminals in the cytosolic phase, and in the glycosylated loop between TMDs I and II. Several motifs involved in

4408-623: The membrane across which they transport substances. The proteins may assist in the movement of substances by facilitated diffusion (i.e., passive transport) or active transport . These mechanisms of movement are known as carrier-mediated transport . Each carrier protein is designed to recognize only one substance or one group of very similar substances. Research suggests that potassium, calcium and sodium channels can function as oxygen sensors in mammals and plants, and has correlated defects in specific carrier proteins with specific diseases. A membrane transport protein (or simply transporter )

4484-428: The neuron from firing an action potential. In this way, the output of a neuron may depend on the input of many different neurons, each of which may have a different degree of influence, depending on the strength and type of synapse with that neuron. John Carew Eccles performed some of the important early experiments on synaptic integration, for which he received the Nobel Prize for Physiology or Medicine in 1963. When

4560-509: The neurotransmitter GABA into the extracellular space. Along the same vein, GABA released from neurogliaform cells into the extracellular space also acts on surrounding astrocytes , assigning a role for volume transmission in the control of ionic and neurotransmitter homeostasis. Approximately 78% of neurogliaform cell boutons do not form classical synapses. This may be the first definitive example of neurons communicating chemically where classical synapses are not present. An electrical synapse

4636-504: The number and replenishment rate of vesicles or it can affect the relationship between calcium and vesicle release. Homosynaptic plasticity can also be postsynaptic in nature. It can result in either an increase or decrease in synaptic strength. One example is neurons of the sympathetic nervous system (SNS), which release noradrenaline , which, besides affecting postsynaptic receptors, also affects presynaptic α2-adrenergic receptors , inhibiting further release of noradrenaline. This effect

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4712-613: The only type of biological synapse : electrical and immunological synapses also exist. Without a qualifier, however, "synapse" commonly refers to chemical synapses. Synapses are functional connections between neurons, or between neurons and other types of cells. A typical neuron gives rise to several thousand synapses, although there are some types that make far fewer. Most synapses connect axons to dendrites , but there are also other types of connections, including axon-to-cell-body, axon-to-axon, and dendrite-to-dendrite . Synapses are generally too small to be recognizable using

4788-470: The other hand, a presynaptic neuron releasing an inhibitory neurotransmitter, such as GABA , can cause an inhibitory postsynaptic potential (IPSP) in the postsynaptic neuron, bringing the membrane potential farther away from the threshold, decreasing its excitability and making it more difficult for the neuron to initiate an action potential. If an IPSP overlaps with an EPSP, the IPSP can in many cases prevent

4864-425: The postsynaptic cell membrane, causing ions to enter or exit the cell and changing the local transmembrane potential . The resulting change in voltage is called a postsynaptic potential . In general, the result is excitatory in the case of depolarizing currents, and inhibitory in the case of hyperpolarizing currents. Whether a synapse is excitatory or inhibitory depends on what type(s) of ion channel conduct

4940-419: The postsynaptic current(s), which in turn is a function of the type of receptors and neurotransmitter employed at the synapse. The second way a receptor can affect membrane potential is by modulating the production of chemical messengers inside the postsynaptic neuron. These second messengers can then amplify the inhibitory or excitatory response to neurotransmitters. After a neurotransmitter molecule binds to

5016-460: The postsynaptic region may be found on the dendrites or cell body. Immediately behind the postsynaptic membrane is an elaborate complex of interlinked proteins called the postsynaptic density (PSD). Proteins in the PSD are involved in anchoring and trafficking neurotransmitter receptors and modulating the activity of these receptors. The receptors and PSDs are often found in specialized protrusions from

5092-412: The presynaptic nerve terminal, vesicles containing neurotransmitter are localized near the synaptic membrane. The arriving action potential produces an influx of calcium ions through voltage-dependent, calcium-selective ion channels at the down stroke of the action potential (tail current). Calcium ions then bind to synaptotagmin proteins found within the membranes of the synaptic vesicles, allowing

5168-467: The residues Lys139 and Asp427 are thought to compose an ion pair that promotes high-affinity interaction with VMAT substrates and inhibitors. The Asp431 residue located in TMD XI is believed to be critical for amine transport, but does not interact with RES binding; it is thought to complete the substrate transport cycle. VMATs have a relatively low V max , with an estimated rate of 5–20/sec depending on

5244-791: The same binding site. VMAT inhibitors tend to fall into two classes: those that interact with the RES binding site and those that interact with the TBZ binding site. RES, methoxytetrabenazine (MTBZ), and the drug amiodarone bind to the RES binding site. TBZ (also called Nitoman and Xenazine), dihydrotetrabenazine (DTBZOH), ketanserin (KET), and the drug lobeline bind to the TBZ binding site. Amphetamine, methamphetamine and GZ-7931 are also known to interact with VMAT2. Inhibitor affinity varies among VMAT isoforms. RES and KET have higher inhibitory affinity for VMAT2–mediated 5HT transport than for that of VMAT1; TBZ seems to inhibit VMAT2 exclusively. The residues asp33 and ser180, 181, and 182 are believed to be involved in substrate recognition, and interact with

5320-589: The same transport mechanism for all types of monoamines, and transport them from the cytosol into high-concentration storage vesicles. Transport vesicles are released into the space between neurons, called the synaptic cleft , where they convey a chemical message to the next neuron. VMATs also function in sorting, storing, and releasing neurotransmitters, and are believed to participate in protecting these neurotransmitters from autoxidation . The transporters are also known to continue biochemical modification after loading certain neurotransmitters. Vesicle packing requires

5396-421: The substrate recognition site from the lumen to the cytoplasmic surface of the vesicle for RES and substrate binding. Methoxytetrabenazine (MTBZ) may bind to the RES binding site, based on studies indicating that RES significantly inhibited MTBZ-binding. Amiodarone is also believed to inhibit monoamine vesicular uptake by binding to the RES binding site. TBZ and dihydrotetrabenazine (DTBZOH) are believed to bind to

5472-406: The substrate. Vesicle filling may limit monoamine release from neurons with high rates of firing. Specific amine-binding affinity varies by VMAT isoform; studies indicate that catecholamines dopamine, norepinephrine, and epinephrine have a threefold higher affinity for VMAT2 than VMAT1 binding and uptake. The imidazoleamine histamine has a thirtyfold higher affinity for VMAT2 compared to VMAT1, and

5548-437: The synaptic cleft by exocytosis . These molecules then bind to neurotransmitter receptors on the postsynaptic cell. Finally, the neurotransmitters are cleared from the synapse through one of several potential mechanisms including enzymatic degradation or re-uptake by specific transporters either on the presynaptic cell or on some other neuroglia to terminate the action of the neurotransmitter. The adult human brain

5624-412: The synaptic strength can be short-term, lasting seconds to minutes, or long-term ( long-term potentiation , or LTP), lasting hours. Learning and memory are believed to result from long-term changes in synaptic strength, via a mechanism known as synaptic plasticity . Desensitization of the postsynaptic receptors is a decrease in response to the same neurotransmitter stimulus. It means that the strength of

5700-412: The vesicles to fuse with the presynaptic membrane. The fusion of a vesicle is a stochastic process, leading to frequent failure of synaptic transmission at the very small synapses that are typical for the central nervous system . Large chemical synapses (e.g. the neuromuscular junction ), on the other hand, have a synaptic release probability, in effect, of 1. Vesicle fusion is driven by the action of

5776-463: The weak base properties of substituted amphetamines. This “Weak Base Hypothesis” proposes that amphetamine analogs enter the cell through transport and lipophilic diffusion, then diffuses through the vesicular membrane where they accumulate in synaptic vesicles and offset the proton electrochemical gradient in the vesicle that drives monoamine transport through VMAT. Amphetamine administration would prevent vesicular dopamine uptake through VMAT, and explain

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