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32-678: The plasma membrane monoamine transporter ( PMAT ) is a low-affinity monoamine transporter protein which in humans is encoded by the SLC29A4 gene . It is known alternatively as the human equilibrative nucleoside transporter-4 (hENT4). It was discovered in 2004 and has been identified as a potential alternate target for treating various conditions. 222962 243328 ENSG00000164638 ENSMUSG00000050822 Q7RTT9 Q8R139 NM_001040661 NM_001300847 NM_153247 NM_146257 NP_001035751 NP_001287776 NP_694979 NP_666369 The plasma membrane monoamine transporter

64-506: A non-selective reuptake inhibitor . Methylphenidate is not an inhibitor of SERT. It has been observed that the pathology of depression involves dysfunction of monoamine neurotransmitter circuits in the CNS, particularly of serotonin and norepinephrine. Selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressant and include fluoxetine (Prozac), citalopram (Celexa), and fluvoxamine (Luvox). These drugs inhibit

96-465: A functional DAT is necessary which suggests that DAT dysfunction may contribute to schizophrenia. DAT is also the target of several "DAT-blockers" including amphetamine and cocaine . These chemicals inhibit the action of DAT and, to a lesser extent, the other monoamine transporters, but their effects are mediated by separate mechanisms. Monoamine transporters are established targets for many pharmacological agents that affect brain function, including

128-639: A net efflux of substrates and ions out of a neuron. To return to an outwardly facing conformation SERT requires the transport of intracellular K . There is no evidence that the other transporters have such a requirement. Phosphorylation plays a key role in MAT function. When SERT is phosphorylated by the PKC-dependent pathway SERT internalization occurs. The internalization of SERT reduces 5-HT uptake. Similar phosphorylation events occur in DAT and NET, decreasing

160-486: A number of existing compounds have been found to act as weak inhibitors of this transporter, with the exception of decynium-22 , which is more potent. These compounds include: Lopinavir shows promising results as a newly discovered selective PMAT inhibitor that does not impact. This membrane protein –related article is a stub . You can help Misplaced Pages by expanding it . Monoamine transporter There are several different monoamine transporters located along

192-850: A potential glycosylation site, and its first 6 transmembrane domains are suspected to be important for substrate recognition. It is not homologous to other known monoamine transporters, such as the high-affinity SERT, DAT, and NET, or the low-affinity SLC22A OCT family. It was initially identified by a search of the draft human genome database through its sequence homology to ENTs (equilibrative nucleoside transporters). Common SSRIs have been shown to inhibit PMAT uptake but at far greater concentrations than SERT. Residual uptake due to incomplete inhibition of PMAT may contribute to SSRI treatment resistance. Mice models with specific constitutive genetic deficiencies in PMAT have demonstrated behavioral changes relative to WT, including upon anti-depressant administration. PMAT

224-419: Is an antidepressant drug that is a relatively selective inhibitor of NE uptake. Studies of inhibition of NET correlate with antidepressant activity. NET regulation is linked to altered dopamine transmission and schizophrenia-like behaviors. Nisoxetine is a NET inhibitor and reverses some schizophrenia-linked behavior. NET activities regulate NE as well as DA equilibrium. In addition, for normal DA clearance

256-440: Is an integral membrane protein that transports the monoamine neurotransmitters ( serotonin , dopamine , norepinephrine ) as well as adenosine , from synaptic spaces into presynaptic neurons or neighboring glial cells . It is abundantly expressed in the human brain, heart tissue, and skeletal muscle, as well as in the kidneys, liver, and small intestine. It is relatively insensitive to the high affinity inhibitors (such as SSRIs) of

288-466: Is attempting to clarify the extent to which kinase cascades, transporter interacting proteins, and phosphorylation contribute to MAT regulation. Below are examples of drugs that act directly by inhibiting two or more MATs simultaneously. Serotonin-norepinephrine re-uptake inhibitors ( SNRIs ) act by blocking both SERTs and NETs. Triple re-uptake inhibitors ( TRIs ) act by blocking DATs, NETs, and SERTs simultaneously. Most modern antidepressant drugs work on

320-508: Is permeable to in a highly pH-dependent manner. In addition to transporting neurotransmitters at synapses, PMAT plays a key role in neurotoxin and drug removal from the cerebrospinal fluid . It is also likely to play a key role in histamine clearance from synapses, specifically through astrocytes. PMAT has 530 amino acid residues with a predicted molecular weight of 58kD, 11 transmembrane segments, an extracellular C-terminus, and an intracellular N-terminus. It has several phosphorylation sites and

352-491: Is possible that PMAT along with standard DAT inhibition could lead to better treatment outcomes with more complete blockage of uptake. PMAT is expressed within the apical membranes of enterocytes in the small intestine. Gene variants affecting the expression of PMAT have been demonstrated to increase the occurrence of GI disturbance side effects with metformin administration, the most common type II diabetes medication. No highly selective PMAT inhibitors are yet available, but

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384-491: The GABA transporter . Current research is underway to understand how MATs function and are regulated by looking at newly discovered structural and functional domains of these proteins. Over the last decade, the availability of targeted disruption of monoamine transporter genes in animal models as well as in vivo imaging approaches have shown progress in studies associated with psychiatric and movement disorders. Ongoing research

416-627: The cerebral cortex , CA1 and CA3 regions of the hippocampus, as well as the median and dorsal raphe nuclei . In the PNS, SERT is localized to the intestinal tract, adrenal glands , placenta, lung, and platelets . Expression of SERT in platelets is used as a means to reacquire 5-HT from the extracellular environment and later used in platelet activation. Regulation of SERT has been linked to acute depletion of intracellular Ca Na , calmodulin inhibition, CaMKII, Src , p38 MAP kinase , PKC, and activation of NOS / cGMP . Monoamine transporters are members of

448-452: The hippocampus and cortex. Peripherally, NET can be found in sympathetic peripheral neurons, the adrenal medulla , the lung, the placenta, and the vas deferens . Regulation of NET has been linked to MAPKs , insulin , PKC, and angiotensin II . SERT is responsible for the reuptake of extracellular serotonin (5-HT) in a Na /Cl -dependent process. In the CNS, SERT is found localized in

480-500: The plasma membrane , each belonging to the family of Na /Cl -dependent substrate-specific neuronal membrane transporters. DAT is responsible for the Na /Cl -dependent reuptake of extracellular dopamine (DA). DATs can be found in the central nervous system (CNS), where they are localized in the substantia nigra and ventral tegmental area (VTA). DATs are also found in the peripheral nervous system ( PNS ) where they are localized in

512-457: The SLC6A monoamine transporters (SERT, DAT, NET), as well being only weakly sensitive to the adenosine transport inhibitor, dipyridamole . PMAT is especially prevalent in dendrites with dense monoaminergic input, and has a significant impact on synaptic clearance of monoamines, especially under non-homeostatic conditions. PMAT transport is electrogenic, utilizing the naturally negative interior of

544-413: The cells to attract the cationic monoamines, thereby increasing its V max (without changing affinity) with increasingly negative membrane potentials. PMAT preferentially transports 5-HT and DA, with a transport efficiency comparable to SERT and DAT, but a with a lower K m . PMAT and similar transporters like OCT3 are commonly referred to as uptake 2 transporters. Uptake 2 transport refers to

576-487: The cells transport capacity of MAs. Monoamine transporters are believed to be factors in several neurological conditions due to their role in reuptake of the monoamines dopamine, noradrenaline, and serotonin. These conditions include ADHD , depression , drug abuse , Parkinson's disease , schizophrenia , and Tourette's syndrome . Evidence supporting this belief includes that monoamine transporters, DAT, NET, and SERT, are important target sites for therapeutic drugs used in

608-597: The group of Na /Cl -dependent substrate-specific neuronal membrane transporters belonging to the SLC6 gene family. MATs are large integral membrane proteins composed of 12 transmembrane domains connected by intracellular and extracellular loops. The NH 2 and COOH termini of the MAT proteins are located within the cytoplasm of presynaptic cells. All MATs contain sites for protein kinase phosphorylation by cAMP -dependent protein kinase, protein kinase C (PKC) and Ca /calmodulin-dependent protein kinase. MATs are responsible for

640-605: The hyperactivity, inattention, and impulsivity in ADHD is related to abnormal DAT function and regulation. Dopaminergic hypofunction in the frontal cortex and basal ganglia is a neurobiological feature observed in ADHD. Psychostimulants that potently inhibit DAT, such as methylphenidate and amphetamine , are efficacious in treating ADHD. Methylphenidate (Ritalin) inhibits both DAT and NET, which results in an increase in extracellular dopamine and norepinephrine that can readily bind postsynaptic cells. Methylphenidate targets DAT as

672-562: The increase in extracellular dopamine. In contrast, amphetamine enters the presynaptic neuron directly through the neuronal membrane or through monoamine transporters, competing for reuptake with neurotransmitters. Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2 . When amphetamine binds to TAAR1, it reduces post-synaptic receptor firing rate and triggers protein kinase A and protein kinase C signaling, resulting in transporter phosphorylation. Phosphorylated transporters then either operate in reverse or withdraw into

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704-410: The pharmacological and functional properties of MAT proteins have been essential in the discovery of therapeutic treatment of many mental disorders. During the 1990s various cloning techniques using MATs have elucidated the genetic structure of these proteins. In 1991 Susan Amara and her colleagues determined the amino acid sequence of NET, discovering its relatively high coding similarities to that of

736-531: The presynaptic neuron and cease transport. When amphetamine enters the synaptic vesicles through VMAT2, monoamines are released into the cytosol. The field of monoamine transporter research began roughly five decades ago with Julius Axelrod 's research on NETs. Axelrod eventually received his Nobel Prize for this research, which led to the discovery of DATs and SERTs as well as consequences associated with antidepressant and psychostimulant interactions with MAT proteins. Since Axelrod's initial studies, understanding

768-413: The principle of blocking re-uptake transporters. SSRI's such as Fluoxetine (Prozac) and SNRI's as with Venlafaxine are the main types of drugs given in first line depression and anxiety treatment. Organic cation transporter (Redirected from Organic cation transporter ) An organic cation transport protein mediates the transport of organic cations across

800-501: The psychostimulants cocaine and amphetamine . Cocaine and amphetamine employ different mechanisms that both result in an increase in extracellular monoamines by decreasing reuptake. Psychostimulants affect primarily DAT, although there is some inhibition at SERT and NET. A large increase of synaptic dopamine results in an increased stimulation of target neurons believed to create the sensations of cocaine. The stimulatory and euphoric effects of cocaine are created when cocaine inhibits

832-443: The reuptake of dopamine by DAT, which results in an increase in extracellular dopamine. Dopamine can then more readily bind neurons, which overstimulates the cells. Cocaine is a non-selective, competitive inhibitor of monoamine transporters, sharing a similar mechanism with that of methylphenidate . Cocaine interacts with DAT, SERT, and NET, although the behavioral and reinforcing effects of cocaine depend on its inhibition of DAT and

864-415: The reuptake of serotonin from the extracellular space into the synaptic terminal by selectively inhibiting SERT. It has been recently observed that serotonin, norepinephrine, and dopamine may all be involved in depression. Therefore, drugs such as venlafaxine and paroxetine are being used as effective antidepressants that selectively inhibit both SERT and NET. The tricyclic antidepressant desipramine

896-456: The stomach, pancreas, as well as in lymphocytes . Various kinases have been linked to DAT regulation including PKA , PKC , PI-3K , ERK1 , ERK2 , Akt , CaMKII , CDK5 , and MAPK . NET is responsible for the Na /Cl -dependent reuptake of extracellular norepinephrine (NE). NET can also reuptake extracellular DA. Within the CNS, NET is localized to the dendrites and axons found in both

928-482: The transport of biogenic amines through low affinity, high-capacity transporters. At low a pH, (5.5-6.5 range, as occurs under ischemic conditions) its transport efficiency increases for all substrates, whereas at high pH (>8) transport is blocked. Unlike other members of the ENT family, it is impermeable to most nucleosides , with the exception of the inhibitory neurotransmitter and ribonucleoside adenosine , which it

960-492: The treatment of mood disorders. Several drugs are used to treat disease symptoms by blocking monoamine transporters, which results in an increase in extracellular monoamines. In addition, the levels of monoamine transporters have been shown to be altered in many of these psychiatric and neurological conditions. Finally, polymorphic variations in monoamine transporter genes have been proposed to be associated with conditions such as ADHD and depression. It has been observed that

992-588: The uptake of monoamines by the sequential binding and co-transport of Na and Cl ions. The ion concentration gradient generated by the plasma membrane Na /K ATPase provides the driving force for the transporter-mediated monoamine uptake. In the case of NET and SERT one Na and one Cl ion are transported into the cell with one NE or 5-HT respectively. In the case of DAT two Na and one Cl ion are transported along with one DA. When ionic gradients are altered (extracellular K increases or extracellular Na or Cl decreases) transporters can function in reverse resulting in

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1024-529: Was demonstrated to be differentially expressed in juvenile or adult mice. This differential expression coincided with decreased SSRI efficacy, and an anti-depressant-like effect of the PMAT inhibitor Decynium-22 , suggesting a tentative mechanism for treatment-resistant depression in human adolescents and children. Parkinson's disease states may be affected by PMAT activity at the synapse, due to its higher affinity for dopamine. In seeking to treat Parkinson's through increasing synaptic dopamine concentrations, it

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