Editing Monoamine transporter

{{Short description|Proteins that function as integral plasma-membrane transporters}}
[[File:Dopamine Transporter.jpg|thumb|280px|right|Dopamine Transporter (DAT-6)]]

'''Monoamine transporters''' ('''MATs''') are [[protein]]s that function as integral [[Cell membrane|plasma-membrane]] [[Neurotransmitter transporter|transporter]]s to regulate concentrations of extracellular [[monoamine neurotransmitter]]s. The three major classes are [[serotonin transporter]]s (SERTs), [[dopamine transporter]]s (DATs), and [[norepinephrine transporter]]s (NETs) and are responsible for the reuptake of their associated amine neurotransmitters ([[serotonin]], [[dopamine]], and [[norepinephrine]]). MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron.<ref name=Torres>{{cite journal|last=Torres|first=Gonzalo E.|author2=Raul R. Gainetdinov |author3=Marc G. Caron |title=Plasma Membrane Monoamine Transporters: Structure, Regulation and Function|journal=Nature Reviews Neuroscience |date=January 2003|volume=4|pages=13–25| doi=10.1038/nrn1008|issue=1|pmid=12511858|s2cid=21545649}}</ref> MAT regulation generally occurs through [[protein phosphorylation]] and [[post-translational modification]].<ref name=rama>{{cite journal | last1 = Ramamoorthy | first1 = Sammanda | last2 = Shippenberg | first2 = Toni | last3 = Jayanthi | first3 = Lankupalle | year = 2010 | title = Regulation of monoamine transporters: Role of transporter phosphorylation | journal = Pharmacology & Therapeutics | volume = 129 | issue = 2| pages = 220–238 | doi=10.1016/j.pharmthera.2010.09.009| pmid = 20951731 | pmc = 3031138 }}</ref>  Due to their significance in neuronal signaling, MATs are commonly associated with [[drugs]] used to [[Psychiatric medication|treat]] [[mental disorders]] as well as [[recreational drugs]]. Compounds targeting MATs range from medications such as the wide variety of [[tricyclic antidepressant]]s, [[selective serotonin reuptake inhibitor]]s such as [[fluoxetine]] (Prozac) to [[stimulant]] medications such as [[methylphenidate]] (Ritalin) and [[amphetamine]] in its many forms (Adderall, Dexedrine) and derivatives [[methamphetamine]] (Desoxyn) and [[lisdexamfetamine]] (Vyvanse). Furthermore, drugs such as [[MDMA]]<ref name="pmid17209801">{{cite journal|vauthors=Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR |title = New insights into the mechanism of action of amphetamines|journal = Annual Review of Pharmacology and Toxicology|volume = 47|pages = 681–98|year = 2007|pmid = 17209801|doi = 10.1146/annurev.pharmtox.47.120505.105140|issue=1}}</ref> ("ecstasy", "molly") and natural alkaloids such as [[cocaine]] exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.<ref name=Torres/><ref>{{cite web|url=http://www.drugbank.com|website=DrugBank|accessdate=19 March 2018}}</ref>

==Types==
There are several different monoamine transporters located along the [[plasma membrane]], each belonging to the family of Na <sup>+</sup>/Cl <sup>−</sup> -dependent substrate-specific neuronal membrane transporters.<ref name=rama/>

* The [[dopamine]] transporter, [[Dopamine transporter|DAT]].
* The [[norepinephrine]] transporter, [[Norepinephrine transporter|NET]].
* The [[serotonin]] transporter, [[Serotonin transporter|SERT]].

==Function==

===Dopamine transporter (DAT)===
{{Main|Dopamine transporter}}
DAT is responsible for the  Na <sup>+</sup>/Cl <sup>−</sup> -dependent reuptake of extracellular dopamine (DA).<ref name=rama/> 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 ([[Peripheral nervous system|PNS]]) where they are localized in the stomach, pancreas, as well as in [[lymphocytes]].<ref name=rama/>  Various [[kinases]] have been linked to DAT regulation including [[Protein kinase A|PKA]], [[Protein kinase C|PKC]], [[PI-3K]], [[ERK1]], [[ERK2]], [[Akt]], [[CaMKII]], [[CDK5]], and [[MAPK]].<ref name=rama/>

===Norepinephrine transporter (NET)===
{{Main|Norepinephrine transporter}}
NET is responsible for the Na <sup>+</sup>/Cl <sup>−</sup> -dependent reuptake of extracellular norepinephrine (NE).<ref name=rama/>  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]].<ref name=Torres/><ref name=rama/>  Regulation of NET has been linked to [[MAPK]]s, [[insulin]], PKC, and [[angiotensin II]].<ref name=rama/>

===Serotonin transporter (SERT)===
{{Main|Serotonin transporter}}
SERT is responsible for the reuptake of extracellular serotonin (5-HT) in a  Na <sup>+</sup>/Cl <sup>−</sup> -dependent process.<ref name=rama/>  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 .<ref name=Torres/><ref name=rama/> 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 <sup>2+</sup>, [[calmodulin]] inhibition, CaMKII, [[Src (gene)|Src]], [[p38 MAP kinase]], PKC, and activation of [[Nitric oxide synthase|NOS]]/[[cyclic guanosine monophosphate|cGMP]].<ref name=rama/>

==Structure and mechanism==
[[File:Dopamine Transporter Crystal Structure.png|thumb|Dopamine transporter crystal structure. Extracellular, transmembrane, and intracellular regions shown in turquoise, blue, and pink, respectively. Based on structure from Penmansta et al. (Nature, 2013)]]
Monoamine transporters are members of the group of Na <sup>+</sup>/Cl <sup>−</sup> -dependent substrate-specific neuronal membrane transporters belonging to the SLC6 gene family.<ref name="pmid31270469">{{cite journal |vauthors=Cheng MH, Bahar I |title=Monoamine transporters: structure, intrinsic dynamics and allosteric regulation |journal=Nat. Struct. Mol. Biol. |volume=26 |issue=7 |pages=545–556 |date=2019 |pmid=31270469 |pmc=6712983 |doi=10.1038/s41594-019-0253-7 }}</ref> MATs are large integral membrane proteins composed of 12 transmembrane domains connected by intracellular and extracellular loops.  The NH<sub>2</sub> and COOH termini of the MAT proteins are located within the cytoplasm of presynaptic cells. All MATs contain sites for protein kinase phosphorylation by [[Cyclic adenosine monophosphate|cAMP]]-dependent protein kinase, protein kinase C (PKC) and Ca<sup>2+</sup>/calmodulin-dependent protein kinase.<ref name=rama/><ref name=Torres/>

MATs are responsible for the uptake of monoamines by the sequential binding and co-transport of Na <sup>+</sup> and Cl <sup>−</sup> ions. The ion concentration gradient generated by the plasma membrane Na<sup>+</sup>/K<sup>+</sup> ATPase provides the driving force for the transporter-mediated monoamine uptake.<ref name=Torres/><ref name=gainet>{{cite journal | last1 = Gainetdinov | first1 = Raul | last2 = Caron | first2 = Marc | year = 2003 | title = Monoamine Transporters: From Genes to Behavior | journal = Annual Review of Pharmacology and Toxicology | volume = 43 | pages = 261–264 | doi=10.1146/annurev.pharmtox.43.050802.112309| pmid = 12359863 | s2cid = 6613675 }}</ref> In the case of NET and SERT one Na<sup>+</sup> and one Cl<sup>−</sup> ion are transported into the cell with one NE or 5-HT respectively. In the case of DAT two Na<sup>+</sup> and one Cl<sup>−</sup> ion are transported along with one DA. When ionic gradients are altered (extracellular K<sup>+</sup> increases or extracellular Na<sup>+</sup> or Cl<sup>−</sup> decreases) transporters can function in reverse resulting in a net efflux of substrates and ions out of a neuron.<ref name=Torres/>

To return to an outwardly facing conformation SERT requires the transport of intracellular K<sup>+</sup>. There is no evidence that the other transporters have such a requirement.<ref name=Torres/>

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.<ref name=rama/>  Similar phosphorylation events occur in DAT and NET, decreasing the cells transport capacity of MAs.

{| class="wikitable"
|-
! MAT !! Gene !! Size !! Human Chromosome
|-
| DAT || hDAT || 620 amino acids || 5p15.3<ref name=rama/>
|-
| SERT || hSERT || 630 amino acids || 17q11.2<ref name=rama/>
|-
| NET || hNET || 617 amino acids || 16q12.2<ref name=rama/>
|}

==Associated disorders and treatments==
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]], [[Major depressive disorder|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 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.<ref name= Sitte>{{cite book|title=Handbook of Neurochemistry and Molecular Neurobiology: Neural Membranes and Transport|year=2007|publisher=Springer Reference|isbn=978-0-387-30347-5|author=H.H. Sitte|edition=3rd|author2=M. Freissmuth|editor=Abel Lajta|chapter=17: Monoamine transporters in the brain: Structure and Function}}</ref>  In addition, the levels of monoamine transporters have been shown to be altered in many of these psychiatric and neurological conditions.  Finally, [[Polymorphism (biology)|polymorphic]] variations in monoamine transporter genes have been proposed to be associated with conditions such as ADHD and depression.<ref name=Torres/>

===Attention deficit hyperactivity disorder===
It has been observed that 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.<ref name=Fone/>  [[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 a [[Reuptake inhibitor|non-selective reuptake inhibitor]].<ref name=rama/>   Methylphenidate is not an inhibitor of SERT.<ref name=Fone>{{cite journal|doi=10.1016/j.coph.2004.10.001|last=Fone|first=Kevin|author2=David J Nutt|title=Stimulants: use and abuse in the treatment of attention deficit hyperactivity disorder|journal=Current Opinion in Pharmacology|date=February 2005|volume=5|issue=1|pages=87–93|pmid=15661631}}</ref>

===Depression===
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 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.<ref name=Nemeroff>{{cite journal|last=Nemeroff|first=Charles B.|author2=Michael J. Owens|title=Treatment of mood disorders|doi=10.1038/nn943 |pmid=12403988|journal=Nature Neuroscience|date=October 2002|pages=1068–1070|volume=5|s2cid=35112132}}</ref>  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.<ref name=Reith>{{cite book|title=Neurotransmitter Transporters|year=1997|publisher=Humana Press Inc.|isbn=0-89603-372-4|author=Maarten E. A. Reith|author-link=Role of Axonal and Somatodendritic Monoamine Transporters in Action of Uptake Blockers|author2=Nian-Hang Chen|editor=Maarten E. A. Reith}}</ref>

===Schizophrenia===
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 a functional DAT is necessary which suggests that DAT dysfunction may contribute to schizophrenia.<ref name=rama/>

==Psychostimulants==
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 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.<ref name= Torres/>

===Cocaine===
The stimulatory and euphoric effects of cocaine are created when cocaine inhibits 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 the increase in extracellular dopamine.<ref name= Torres/>

===Amphetamine===
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 [[trace amine-associated receptor 1|TAAR1]] or enters synaptic vesicles through [[vesicular monoamine transporter 2|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 the presynaptic neuron and cease transport.  When amphetamine enters the synaptic vesicles through VMAT2, monoamines are released into the cytosol.<ref name="Miller">{{cite journal | author = Miller GM | title = The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity | journal = J. Neurochem. | volume = 116 | issue = 2 | pages = 164–76 |date=January 2011 | pmid = 21073468 | pmc = 3005101 | doi = 10.1111/j.1471-4159.2010.07109.x }}</ref><ref name="E Weihe">{{cite journal |vauthors=Eiden LE, Weihe E | title = VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse | journal = Ann. N. Y. Acad. Sci. | volume = 1216 | issue = 1| pages = 86–98 |date=January 2011 | pmid = 21272013 | doi = 10.1111/j.1749-6632.2010.05906.x | pmc=4183197| bibcode = 2011NYASA1216...86E }}</ref>

==Research history==
The field of monoamine transporter research began roughly five decades ago{{clarify timeframe|date=February 2022}} 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 the pharmacological and functional properties of MAT proteins have been essential in the discovery of therapeutic treatment of many mental disorders.<ref name=Torres/>  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 the [[GABA transporter]].<ref name=Torres/>

Current research is underway to understand how MATs function and are regulated by looking at newly discovered structural and functional domains of these proteins.<ref name=Torres/><ref name=Hahn>{{cite journal|doi=10.1038/sj.tpj.6500106|last=Hahn|first=MK|author2=RD Blakely|title=Monoamine Transporter Gene Structure and Polymorphisms in Relation to Psychiatric and Other Complex Disorders|journal=The Pharmacogenomics Journal|date=5 March 2002|volume=2|issue=4|pages=217–235|pmid=12196911|doi-access=|s2cid=24247634 }}</ref> 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.<ref name=Torres/>  Ongoing research is attempting to clarify the extent to which kinase cascades, transporter interacting proteins, and phosphorylation contribute to MAT regulation.<ref name=rama/>

[[Image:JZ-IV-10 chemical structure.png|180px|thumb|'''16e''']][[Image:Phenyltropane Carroll 4b.svg|220px|thumb|Blough 2002]]

==Double and triple MAT agents ({{aka}} SNRIs and TRIs)==
Below are examples of drugs that act directly by inhibiting two or more MATs simultaneously. Serotonin-norepinephrine re-uptake inhibitors ([[Serotonin–norepinephrine reuptake inhibitor|SNRIs]]) act by blocking both SERTs and NETs. Triple re-uptake inhibitors ([[Triple reuptake inhibitors|TRIs]]) act by blocking DATs, NETs, and SERTs simultaneously. Most modern antidepressant drugs work on 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.

* [[PRC200-SS]] is an example of an SNRI.
* [[JNJ-7925476]] is an example of a TRI
* [[nocaine]]-[[modafinil]] hybrids such as 16e<ref>{{cite journal | last1 = Zhou | first1 = J | last2 = He | first2 = R | last3 = Johnson | first3 = KM | last4 = Ye | first4 = Y | last5 = Kozikowski | first5 = AP | date = Nov 2004 | title = Piperidine-based nocaine/modafinil hybrid ligands as highly potent monoamine transporter inhibitors: efficient drug discovery by rational lead hybridization | journal = Journal of Medicinal Chemistry | volume = 47 | issue = 24| pages = 5821–4 | doi = 10.1021/jm040117o | pmid = 15537337 | pmc=1395211}}</ref><ref name="pmid16335921">{{cite journal |vauthors=He R, Kurome T, Giberson KM, Johnson KM, Kozikowski AP |title=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 |journal=J. Med. Chem. |volume=48 |issue=25 |pages=7970–9 |year=2005 |pmid=16335921 |doi=10.1021/jm050694s }}</ref>
* Blough (2002) showed that MATs exhibit a "remote phenyl binding domaine"<ref name="pmid12190324">{{cite journal |vauthors=Blough BE, Keverline KI, Nie Z, Navarro H, Kuhar MJ, Carroll FI |title=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 |journal=J. Med. Chem. |volume=45 |issue=18 |pages=4029–37 |year=2002 |pmid=12190324|doi=10.1021/jm020098n}}</ref>

==See also==
* [[Vesicular monoamine transporter]] (VMAT)
* [[Plasma membrane monoamine transporter]] (PMAT)
* [[Extraneuronal monoamine transporter]] (EMT)

==References==
{{Reflist|2}}

==External links==
*{{Commons category-inline|Monoamine transporters}}

{{Neurotransmitter transporters}}
{{Monoamine reuptake inhibitors}}
{{Monoamine releasing agents}}

{{DEFAULTSORT:Monoamine Transporter}}
[[Category:Neurotransmitter transporters]]
[[Category:Integral membrane proteins]]