Monoamine transporter
Monoamine transporters (MAT) are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular biogenic monoamine neurotransmitters. Three major classes of MATs (SERT, DAT, NET) are responsible for the reuptake of their cognate amine neurotransmitter (5-HT, dopamine, norepinephrine). MATs are located peri-synaptically, transporting monoamine transmitter overflow from the synaptic cleft to the cytoplasm of the pre-synaptic neuron.[1] MATs regulation generally occurs through phosphorylation and post-translational 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].
Types
There are several different monoamine transporters each belonging to the family of Na +/Cl - -dependent substrate-specific neuronal membrane transporters.
- The dopamine transporter, DAT.
- The norepinephrine transporter, NET.
- The serotonin transporter, SERT.
- The less-specific monoamine transporter, PMAT.
Function
Dopamine transporter (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 kinases have been linked to DAT regulation including PKA, PKC, PI-3K, ERK1, ERK2, Akt, CaMKII, CDK5, and MAPK.[2]
Norepinephrine transporter (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 cortex. Peripherally, NET can be found in sympathetic peripheral neurons, the 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]
Serotonin transporter (SERT) is responsible for the reuptake of extracellular serotonin (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 , lung , and platelets .[2][1] 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 2+, calmodulin inhibition, CaMKII, Src, p38 MAP kinase, PKC, and activation of NOS/cGMP.[2]
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 composed of 12 transmembrane domains connected by intracellular and extracellular loops. The NH2 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 Ca2+/calmodulin-dependent protein kinase.[1]
MATs are responsible for 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.[1] [3] 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 a net efflux of substrates and ions our of a neuron.
| MAT | Gene | Size | Human Chromosome |
|---|---|---|---|
| DAT | hDAT | 620 amino acids | 5p15.3 |
| SERT | hSERT | 630 amino acids | 17q11.2 |
| NET | hNET | 617 amino acids | 16q12.2 |
Associated Disorders and Treatments
Monoamine Transporters are believed to play a role in several neurological diseases due to its role in reuptake of the monoamines: dopamine, noradrenaline, and 5-hydroxytryptamine. ADHD, depression, drug abuse, Parkinson’s disease, Schizophrenia, and Tourette's syndrome are diseases believed to be associated with monoamine transporter functioning. Evidence supporting this belief includes that monoamine transporters, DAT, NET, and SERT, are important target site for therapeutic drugs used in 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[4] . 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[1].
Attention deficit hyperactivity disorder (ADHD)
It has been observed 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 observed in ADHD. Psychostimulants, methylphenidate and amphetamines, which potently inhibit DAT are efficacious in treating ADHD. Methylphenidate (Ritalin) inhibits both DAT and NET, which result in an increase in extracellular dopamine and norepinephrine that can readily bind postsynaptic cells. Methylphenidate targets DAT as a non-selective reuptake inhibitor[2]. Methylphenidate is not an inhibitor of SERT (Fone).
Depression
It has been observed that 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. These drugs inhibit 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[5] . The tricyclic antidepressant desipramine is an antidepressant drug that is a relatively selective inhibitor of NE uptake. Studies of inhibition of NET correlate with antidepressant activity[6] .
Parkinson’s Disease
It has been observed that DA is absent in the basal ganglia of patients with Parkinson’s Disease. Furthermore, there is a lower density of DAT in the brain of a patient afflicted with Parkinson’s Disease[6].
Schizophrenia
NET regulation is linked to altered dopamine transmission and schizophrenia like behaviors. The NET blocker, nisoxetine reverses schizophrenia-linked behavior. Thus, NET activities regulate NE as well as DA homeostasis. In addition, for normal DA clearance a functional DAT is necessary which suggests that DAT dysfunction may contribute to shizophrenia[2]. Furthermore, it has been observed that ampehtamines, which increase extracellular dopamine exacerbate the symptoms of schizophrenia.
Psychostimulants
Pharmacology
Many drugs, such as antidepressants and psychoactives affect the monoamine transporters (MATs).
Modern antidepressants typically work by enhancing serotonergic, noradrenergic or dopaminergic neurotransmission by binding to the corresponding transporter, and thereby inhibiting neurotransmitter reuptake and raising active levels in the synapse. Examples include fluoxetine, a selective serotonin reuptake inhibitor; reboxetine, a norepinephrine reuptake inhibitor and bupropion, which binds to the norepinephrine and dopamine transporter and inhibits reuptake.
The euphoric and addictive properties of amphetamine, methamphetamine and cocaine are thought to come from their potent DAT-blocking activity.
Research History
Triple MAT agents (aka SNDRI's oder TRI)
- Blough (2002) showed that MATs exhibit a "remote phenyl binding domaine"[9]
See also
References
- ^ a b c d e f g Torres, Gonzalo E. (2003). "Plasma Membrane Monoamine Transporters: Structure, Regulation and Function". Nature. 4: 13–25.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ a b c d e f g h i j k l m Ramamoorthy, Sammanda, Toni Shippenberg, and Lankupalle Jayanthi. "Regulation of monoamine transporters: Role of transporter phosphorylation." Pharmacology & Therapeutics 129 (2010): 220-238. Print.
- ^ Gainetdinov, Raul, and Marc Caron. "Monoamine Transporters: From Genes to Behavior." The Annual Review of Pharmacology and Toxicology 43 (2003): 261-264. Print.
- ^ H.H. Sitte (2007). "17: Monoamine transporters in the brain: Structure and Function". In Abel Lajta (ed.). Handbook of Neurochemistry and Molecular Neurobiology: Neural Membranes and Transport (3rd Edition ed.). Springer Reference. ISBN 978-0-387-30347-5.
{{cite book}}:|edition=has extra text (help); Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Nemeroff, Charles B. (2002). "Treatment of mood disorders". Nature neuroscience: 1068–1070.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ a b Maarten E. A. Reith (1997). Maarten E. A. Reith (ed.). Neurotransmitter Transporters. Humana Press Inc. ISBN 0-89603-372-4.
{{cite book}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Zhou J, He R, Johnson KM, Ye Y, Kozikowski AP. Piperidine-based nocaine/modafinil hybrid ligands as highly potent monoamine transporter inhibitors: efficient drug discovery by rational lead hybridization. Journal of Medicinal Chemistry. 2004 Nov 18;47(24):5821-4. PMID 15537337
- ^ He R, Kurome T, Giberson KM, Johnson KM, Kozikowski AP (2005). "Further structure-activity relationship studies of piperidine-based monoamine transporter inhibitors: effects of piperidine ring stereochemistry on potency. Identification of norepinephrine transporter selective ligands and broad-spectrum transporter inhibitors". J. Med. Chem. 48 (25): 7970–9. doi:10.1021/jm050694s. PMID 16335921.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Blough BE, Keverline KI, Nie Z, Navarro H, Kuhar MJ, Carroll FI (2002). "Synthesis and transporter binding properties of 3beta-[4'-(phenylalkyl, -phenylalkenyl, and -phenylalkynyl)phenyl]tropane-2beta-carboxylic acid methyl esters: evidence of a remote phenyl binding domain on the dopamine transporter". J. Med. Chem. 45 (18): 4029–37. doi:10.1021/jm020098n. PMID 12190324.
{{cite journal}}: CS1 maint: multiple names: authors list (link)
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