B y P e t e r X u Monoamine transporter
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Dopamine Transporter (DAT-6)
Monoamine transporters (MATs ) are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters . Three major class of MATs (SERT, DAT, NET) are responsible for the reuptake of their associated amine neurotransmitters (rotonin , dopamine, norepinephrine). MATs are located just outside the synaptic cl
ani difrancoeft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron.[1] MAT regulation generally occurs through phosphorylation and posttranslational modification .[2] Due to their significance in neuronal signaling, MATs are the targets of many therapeutic drugs associated with mood disorders such as fluoxetine (Prozac) and methylphenidate (Ritalin). Synthetic compounds such as methamphetamine and cocaine can also target MATs.[1] Contents [hide ]
• 1 Types • 2 Function o 2.1 Dopamine transporter (DAT) o 2.2 Norepinephrine transporter (NET) er (SERT)o 2.3 Serotonin transport • 3 Structure and mechanism • 4 Associated disorders and treatments o 4.1 Attention deficit hyperactivity disorder
B y P e t e r X u o 4.2 Depression o 4.3 Schizophrenia • 5 Psychostimulants o 5.1 Cocaine o 5.2 Amphetamines • 6 Rearch history • 7 Double and triple MAT agents (aka SNRIs and TRIs)• 8 See also • 9 References [edit ] Types
mily of Na +/Cl - -dependent substrate-specific neuronal membrane transporters.[2]There are veral different monoamine transporters each belonging to the fa •strategic
The dopamine transporter, DAT . •
psbThe norepinephrine transporter, NET . • The rotonin transporter, SERT .
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[edit ] Function
[edit ] Dopamine transporter (DAT)
DAT is responsible for the Na +/Cl - -dependent reuptake of extracellular dopamine (DA).[2] DAT can also transport extracellular norepinephrine. 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 the stomach, pancreas, as well as in lymphocytes .[2] Various kinas have been linked to DAT regulation
including PKA , PKC , PI-3K , ERK1, ERK2, Akt , CaMKII , CDK5, and MAPK .[2]
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[edit ] Norepinephrine transporter (NET)
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NET is responsible for the Na +/Cl - -dependent reuptake of extracellular
norepinephrine (NE).[2] NET can also reuptake extracellular DA. Within the CNS, NET is localized to the dendrites and axons found in both the hippocampus and Peripherally, NET can be found in sympathetic peripheral neurons, the cortex. adrenal medulla , the lung, the placenta, and the vas deferens .[1][2] Regulation of NET has been linked to MAPKs , insulin , PKC, and angiotensin II .[2]
[edit ] Serotonin transporter (SERT)
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e t e r X u SERT is responsible for the reuptake o
f extracellular rotonin (5-HT) in a Na +/Cl - -dependent process.[2] In the CNS, SERT is found localized in 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 , lun
g , and platelets .[1][2] Expression of SERT in platelets is ud as a means to reacquire 5-HT from the extracellular environment and later ud in platelet activation. Regulation of SERT has been linked to acute depletion of intracellular Ca Na 2+, calmodulin inhibition, CaMKII, Src , p38 MAP kin
a , PKC, and activation of NOS /cGMP .[2] [edit ] Structure and mechanism Monoamine transporters are members of the group of Na +/Cl - -dependent substrate-specific neuronal membrane transporters belonging to the SLC6 gene family.[2] MATs are large integral membrane proteins compod 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 kina phosphorylation by cAMP -dependent protein kina, protein kina C (PKC) and Ca 2+/calmodulin-dependent protein kina.[1] MATs are responsible for the uptake of monoamines by the quential binding and co-transport of Na + and Cl - ions. The ion concentration gradient generated by the plasma membrane Na +/K + ATPa provides the driving force for the
transporter-mediated monoamine uptake.[1][3] In the ca of NET and SERT one Na + and one Cl - ion are transported into the cell with one NE or 5-HT respectively. In the ca of DAT two Na + and one Cl - ion are transported along with one DA. When ionic gradients are altered (extracellular K + increas or extracellular Na + or Cl - decreas) transporters can function in rever resulting in a net efflux of substrates and ions out of a neuron.[1]
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.[1]
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.[2] Similar phosphorylation events occur in DAT and NET, decreasing the cells transport capacity of MAs. MAT Gene Size Human Chromosome DAT hDAT 620 amino acids 5p15.3[2]
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18youngchinagirls国SERT hSERT 630 amino acids 17q11.2[2]
NET hNET 617 amino acids 16q12.2[2]
B y P e t e r X u [edit ] Associated disorders and treatments
Monoamine transporters are believed to be factors in veral neurological conditions due to their role in reuptake of the monoamines dopamine, noradrenaline, and 5-hydroxytryptamine. The conditions include ADHD , depression , drug abu , Parkinson’s dia , Schizophrenia , and Tourette's syndrome . Evidence supporting this belief includes that monoamine transporters, DAT, NET, and S are important target sites for therapeutic drugs ud in the treatment of mood disorders.
Several drugs are ud to treat dia symptoms by blocking monoamine transporters, which results in an increa in extracellular monoamines.ERT, [4] In addition, the levels of monoamine transporters have been shown to be altered in many of the psychiatric and neurological conditions. Finally, polymorphic variations in
monoamine transporter genes have been propod to be associated with conditions such as ADHD and depression.[1]
often[edit ] Attention deficit hyperactivity disorder
It has been obrved that the hyperactivity, inattention, and impulsivity in ADHD is related to abnormal DAT function and regulation. Dopaminergic hypofuction in the frontal cortex and basal ganglia is a neurobiological feature obrved in
ADHD.[5] Psychostimulants , methylphenidate and amphetamines , which potently inhibit DAT are efficacious in treating ADHD. Methylphenidate (Ritalin) inhibits both DAT and NET, which results in an increa in extracellular dopamine and norepinephrine that can readily bind postsynaptic cells. Methylphenidate targets DAT as a non-lective reuptake inhibitor .[2] Methylphenidate is not an inhibitor of SERT.[5]
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[edit ] Depression
It has been obrved that the pathology of depression involves dysfunction of monoamine neurotransmitter circuits in the CNS, particularly of rotonin and norepinephrine. Selective rotonin reuptake inhibitors (SSRIs) are the most w ud antidepressant and include idely fluoxetine (Prozac), citalopram (Celexa), and fluvoxamine . The drugs inhibit the reuptake of rotonin from the extracellular space into the synaptic terminal by lectively inhibiting SERT. It has been rec obrved that rotonin, norepinephrine, and dopamine may all be involved in depression. Therefore, drugs such as ently venlafaxine and paroxetine are being ud as effective antidepressants that lectively inhibit both SERT and NET.[6] The tricyclic antidepressant desipramine is an antidepressant drug that is a relatively lective inhibitor of NE uptake. Studies of inhibition of NET correlate with antidepressant activity.[7] [edit ] Schizophrenia
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e t e r X u NET regulation is linked to altered dopamine transmission and schizophrenia-like behaviors. Nisoxetine is a NET inhibitor and revers some schizophrenia-linked behavior. NET activities regulate NE as well as DA equilibrium. In addition, for normal DA clearance a functional DAT is necessary which suggests that DAT dysfunction may contribute to schizophrenia.[2]
[edit ] Psychostimulants
Mechanisms of Cocaine and Amphetamine DAT blocking
DAT is also the target of veral “DAT-blockers” including amphetamines and cocaine . The chemicals inhibit the action of DAT and, to a lesr extent, the other monoamine transporters, but their effects are mediated by parate mechanisms. Monoamine transporters are established targets for many pharmacological agents that affect brain function, including the psychostimulants cocaine and amphetamines . Cocaine and amphetamines employ different mechanisms that both result in an increa in extracellular monoamines by decreasing reuptake. Psychostimulants affect primarily DAT, although there is some inhibition at SERT and NET. Large increas in synaptic dopamine result in incread stimulation of target neurons believed to create the nsations of cocaine and amphetamines.[1]
[edit ] Cocaine The stimulatory and euphoric effects of cocaine are created when cocaine inhibits the reuptake of dopamine by DAT, which results in an increa in extracellular dopamine. Dopamine can then more readily bind neurons, which overstimulates the cells. Cocaine is a a non-lective, competitive inhibitor of monoamine transporters. Cocaine interacts with DAT, SERT, and NET, although the behavioral and
