Plasma membrane monoamine transporter

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The plasma membrane monoamine transporter (PMAT) is a low-affinity monoamine transporter protein which in humans is encoded by the SLC29A4 gene. [1] It is known alternatively as the human equilibrative nucleoside transporter-4 (hENT4). It was discovered in 2004 [2] and has been identified as a potential alternate target for treating various conditions. [3] [4]

Contents

SLC29A4
Identifiers
Aliases SLC29A4 , ENT4, PMAT, solute carrier family 29 member 4, Plasma membrane monoamine transporter
External IDs OMIM: 609149 MGI: 2385330 HomoloGene: 71345 GeneCards: SLC29A4
Orthologs
SpeciesHumanMouse
Entrez

222962

243328

Ensembl

ENSG00000164638

ENSMUSG00000050822

UniProt

Q7RTT9

Q8R139

RefSeq (mRNA)

NM_001040661
NM_001300847
NM_153247

NM_146257

RefSeq (protein)

NP_001035751
NP_001287776
NP_694979

NP_666369

Location (UCSC) Chr 7: 5.27 – 5.31 Mb Chr 5: 142.68 – 142.71 Mb
PubMed search [7] [8]
Wikidata
View/Edit Human View/Edit Mouse

Structure and function

The plasma membrane monoamine transporter is an integral membrane protein that transports the monoamine neurotransmitters (serotonin, dopamine, norepinephrine) as well as adenosine, [9] from synaptic spaces into presynaptic neurons or neighboring glial cells. [10] It is abundantly expressed in the human brain, [11] heart tissue, and skeletal muscle, as well as in the kidneys, liver, and small intestine. [12] It is relatively insensitive to the high affinity inhibitors (such as SSRIs) of 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, [13] and has a significant impact on synaptic clearance of monoamines, especially under non-homeostatic conditions. [10] [14] PMAT transport is electrogenic, utilizing the naturally negative interior of the cells to attract the cationic monoamines, thereby increasing its Vmax (without changing affinity) with increasingly negative membrane potentials. [12] [15]

PMAT preferentially transports 5-HT and DA, [14] with a transport efficiency comparable to SERT and DAT, but a with a lower Km. [3] PMAT and similar transporters like OCT3 are commonly referred to as uptake2 transporters. Uptake2 transport refers to the transport of biogenic amines through low affinity, high-capacity transporters. [3] 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. [12] [15] 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 is permeable to in a highly pH-dependent manner. [16] In addition to transporting neurotransmitters at synapses, PMAT plays a key role in neurotoxin and drug removal from the cerebrospinal fluid. [15] It is also likely to play a key role in histamine clearance from synapses, specifically through astrocytes. [10]

PMAT's proposed structure. PMAT.jpg
PMAT's proposed structure.

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. [15] [12] [17] It has several phosphorylation sites and a potential glycosylation site, and its first 6 transmembrane domains are suspected to be important for substrate recognition. [15] 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. [3] It was initially identified by a search of the draft human genome database through its sequence homology to ENTs (equilibrative nucleoside transporters). [17]

Clinical significance

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. [3] [14] Mice models with specific constitutive genetic deficiencies in PMAT have demonstrated behavioral changes relative to WT, including upon anti-depressant administration. [14] PMAT 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. [18]

Parkinson's disease states may be affected by PMAT activity at the synapse, due to its higher affinity for dopamine. [4] In seeking to treat Parkinson's through increasing synaptic dopamine concentrations, it is possible that PMAT along with standard DAT inhibition could lead to better treatment outcomes with more complete blockage of uptake. [4]

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. [19] [12]

Inhibitors

No highly selective PMAT inhibitors are yet available, but 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: [2]

Lopinavir [10] shows promising results as a newly discovered selective PMAT inhibitor that does not impact. [21]

Substrates

See also

Related Research Articles

<span class="mw-page-title-main">Reuptake</span> Reabsorption of a neurotransmitter by a neurotransmitter transporter

Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal or glial cell after it has performed its function of transmitting a neural impulse.

<span class="mw-page-title-main">Monoamine transporter</span> Proteins that function as integral plasma-membrane transporters

Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters. 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. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA 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.

<span class="mw-page-title-main">Serotonin transporter</span> Mammalian protein found in humans

The serotonin transporter also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein that transports the neurotransmitter serotonin from the synaptic cleft back to the presynaptic neuron, in a process known as serotonin reuptake.

<span class="mw-page-title-main">Serotonin–norepinephrine reuptake inhibitor</span> Class of antidepressant medication

Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, social phobia, chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. Off-label uses include treatments for attention-deficit hyperactivity disorder (ADHD), obsessive–compulsive disorder (OCD), and migraine prevention. SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs), which act upon single neurotransmitters.

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 a proton gradient generated by V-ATPases in vesicle membranes to power monoamine import.

<span class="mw-page-title-main">Norepinephrine transporter</span> Protein-coding gene in the species Homo sapiens

The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene.

Neurotransmitter transporters are a class of membrane transport proteins that span the cellular membranes of neurons. Their primary function is to carry neurotransmitters across these membranes and to direct their further transport to specific intracellular locations. There are more than twenty types of neurotransmitter transporters.

<span class="mw-page-title-main">Phenyltropane</span> Class of chemical compounds

Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.

A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.

<span class="mw-page-title-main">Serotonin reuptake inhibitor</span> Class of drug

A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin by blocking the action of the serotonin transporter (SERT). This in turn leads to increased extracellular concentrations of serotonin and, therefore, an increase in serotonergic neurotransmission. It is a type of monoamine reuptake inhibitor (MRI); other types of MRIs include dopamine reuptake inhibitors and norepinephrine reuptake inhibitors.

A neurotransmitter sodium symporter (NSS) (TC# 2.A.22) is type of neurotransmitter transporter that catalyzes the uptake of a variety of neurotransmitters, amino acids, osmolytes and related nitrogenous substances by a solute:Na+ symport mechanism. The NSS family is a member of the APC superfamily. Its constituents have been found in bacteria, archaea and eukaryotes.

<span class="mw-page-title-main">Nisoxetine</span> Chemical compound

Nisoxetine, originally synthesized in the Lilly research laboratories during the early 1970s, is a potent and selective inhibitor for the reuptake of norepinephrine (noradrenaline) into synapses. It currently has no clinical applications in humans, although it was originally researched as an antidepressant. Nisoxetine is now widely used in scientific research as a standard selective norepinephrine reuptake inhibitor. It has been used to research obesity and energy balance, and exerts some local analgesia effects.

<span class="mw-page-title-main">Reuptake inhibitor</span> Type of drug

Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

<span class="mw-page-title-main">Serotonin–dopamine reuptake inhibitor</span> Class of drug

A serotonin–dopamine reuptake inhibitor (SDRI) is a type of drug which acts as a reuptake inhibitor of the monoamine neurotransmitters serotonin and dopamine by blocking the actions of the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of serotonin and dopamine, and, therefore, an increase in serotonergic and dopaminergic neurotransmission.

A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

The pharmacology of antidepressants is not entirely clear. The earliest and probably most widely accepted scientific theory of antidepressant action is the monoamine hypothesis, which states that depression is due to an imbalance of the monoamine neurotransmitters. It was originally proposed based on the observation that certain hydrazine anti-tuberculosis agents produce antidepressant effects, which was later linked to their inhibitory effects on monoamine oxidase, the enzyme that catalyses the breakdown of the monoamine neurotransmitters. All currently marketed antidepressants have the monoamine hypothesis as their theoretical basis, with the possible exception of agomelatine which acts on a dual melatonergic-serotonergic pathway. Despite the success of the monoamine hypothesis it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, there are a sizeable portion (>40%) of depressed patients that do not adequately respond to monoaminergic antidepressants. Further evidence to the contrary of the monoamine hypothesis are the recent findings that a single intravenous infusion with ketamine, an antagonist of the NMDA receptor — a type of glutamate receptor — produces rapid, robust and sustained antidepressant effects. Monoamine precursor depletion also fails to alter mood. To overcome these flaws with the monoamine hypothesis a number of alternative hypotheses have been proposed, including the glutamate, neurogenic, epigenetic, cortisol hypersecretion and inflammatory hypotheses. Another hypothesis that has been proposed which would explain the delay is the hypothesis that monoamines don't directly influence mood, but influence emotional perception biases.

<span class="mw-page-title-main">Decynium-22</span> Cationic derivative of quinoline

Decynium-22 is a cationic derivative of quinoline, and a potent inhibitor of the plasma membrane monoamine transporter (PMAT), as well as all members of the organic cation transporter (OCT) family in both human and rat cells. However, it has little effect on high affinity monoamine transporters such as the dopamine transporter and norepinephrine transporter.

Selective serotonin reuptake inhibitors, or serotonin-specific re-uptake inhibitor (SSRIs), are a class of chemical compounds that have application as antidepressants and in the treatment of depression and other psychiatric disorders. SSRIs are therapeutically useful in the treatment of panic disorder (PD), posttraumatic stress disorder (PTSD), social anxiety disorder, obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PMDD), and anorexia. There is also clinical evidence of the value of SSRIs in the treatment of the symptoms of schizophrenia and their ability to prevent cardiovascular diseases.

Members of the Equilibrative Nucleoside Transporter (ENT) Family are transport proteins that are specific to nucleosides and nucleobases, and are part of the major facilitator superfamily. They generally possess at least 6, typically 10, transmembrane segments (TMSs) and are 300-600 amino acyl residues in length.

References

  1. ↑ Baldwin SA, Beal PR, Yao SY, King AE, Cass CE, Young JD (February 2004). "The equilibrative nucleoside transporter family, SLC29". Pflügers Archiv. 447 (5): 735–743. doi:10.1007/s00424-003-1103-2. PMID   12838422. S2CID   8817821.
  2. 1 2 Engel K, Wang J (November 2005). "Interaction of organic cations with a newly identified plasma membrane monoamine transporter". Molecular Pharmacology. 68 (5): 1397–1407. doi:10.1124/mol.105.016832. PMID   16099839. S2CID   26542965.
  3. 1 2 3 4 5 6 7 8 9 10 Daws LC (January 2009). "Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for antidepressant efficacy". Pharmacology & Therapeutics. 121 (1): 89–99. doi:10.1016/j.pharmthera.2008.10.004. PMC   2739988 . PMID   19022290.
  4. 1 2 3 Nishijima H, Tomiyama M (2016). "What Mechanisms Are Responsible for the Reuptake of Levodopa-Derived Dopamine in Parkinsonian Striatum?". Frontiers in Neuroscience. 10: 575. doi: 10.3389/fnins.2016.00575 . PMC   5156842 . PMID   28018168.
  5. 1 2 3 GRCh38: Ensembl release 89: ENSG00000164638 - Ensembl, May 2017
  6. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000050822 - Ensembl, May 2017
  7. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  8. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  9. ↑ Xia L, Zhou M, Kalhorn TF, Ho HT, Wang J (June 2009). "Podocyte-specific expression of organic cation transporter PMAT: implication in puromycin aminonucleoside nephrotoxicity". American Journal of Physiology. Renal Physiology. 296 (6): F1307–F1313. doi:10.1152/ajprenal.00046.2009. PMC   2692440 . PMID   19357181.
  10. 1 2 3 4 5 6 7 8 9 10 Furihata T, Anzai N (2017). "Functional Expression of Organic Ion Transporters in Astrocytes and Their Potential as a Drug Target in the Treatment of Central Nervous System Diseases". Biological & Pharmaceutical Bulletin. 40 (8): 1153–1160. doi: 10.1248/bpb.b17-00076 . PMID   28768996.
  11. ↑ Dahlin A, Xia L, Kong W, Hevner R, Wang J (May 2007). "Expression and immunolocalization of the plasma membrane monoamine transporter in the brain". Neuroscience. 146 (3): 1193–1211. doi:10.1016/j.neuroscience.2007.01.072. PMC   2683847 . PMID   17408864.
  12. 1 2 3 4 5 6 Wagner DJ, Hu T, Wang J (September 2016). "Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics". Pharmacological Research. 111: 237–246. doi:10.1016/j.phrs.2016.06.002. PMC   5293005 . PMID   27317943.
  13. ↑ Muma NA, Mi Z (July 2015). "Serotonylation and Transamidation of Other Monoamines". ACS Chemical Neuroscience. 6 (7): 961–969. doi:10.1021/cn500329r. PMID   25615632.
  14. 1 2 3 4 Weber BL, Beaver JN, Gilman TL (November 2023). "Summarizing studies using constitutive genetic deficiency to investigate behavioural influences of uptake 2 monoamine transporters". Basic & Clinical Pharmacology & Toxicology. 133 (5): 439–458. doi:10.1111/bcpt.13810. PMC   10657738 . PMID   36316031.
  15. 1 2 3 4 5 Wang J (November 2016). "The plasma membrane monoamine transporter (PMAT): Structure, function, and role in organic cation disposition". Clinical Pharmacology and Therapeutics. 100 (5): 489–499. doi:10.1002/cpt.442. PMC   5305120 . PMID   27506881.
  16. ↑ Zhou M, Duan H, Engel K, Xia L, Wang J (October 2010). "Adenosine transport by plasma membrane monoamine transporter: reinvestigation and comparison with organic cations". Drug Metabolism and Disposition. 38 (10): 1798–1805. doi:10.1124/dmd.110.032987. PMC   2957165 . PMID   20592246.
  17. 1 2 Engel K, Zhou M, Wang J (November 2004). "Identification and characterization of a novel monoamine transporter in the human brain". The Journal of Biological Chemistry. 279 (48): 50042–50049. doi: 10.1074/jbc.M407913200 . PMID   15448143.
  18. ↑ Bowman MA, Gomez JA, Mitchell NC, Wells AM, Vitela M, Clarke KM, et al. (August 2022). "Faster Serotonin Clearance in CA3 Region of Hippocampus and Antidepressant-like Effect of Decynium-22 in Juvenile Mice Are Putatively Linked to Increased Plasma Membrane Monoamine Transporter Function: Implications for Efficacy of Antidepressants in Juveniles". Cells. 11 (15): 2454. doi: 10.3390/cells11152454 . PMC   9368098 . PMID   35954298.
  19. ↑ Baye AM, Fanta TG, Siddiqui MK, Dawed AY (2021-06-14). "The Genetics of Adverse Drug Outcomes in Type 2 Diabetes: A Systematic Review". Frontiers in Genetics. 12: 675053. doi: 10.3389/fgene.2021.675053 . PMC   8236944 . PMID   34194474.
  20. ↑ Zhu S, Lei S, Zhou S, Jin L, Zeng S, Jiang H, Zhou H (March 2019). "Luteolin shows antidepressant-like effect by inhibiting and downregulating plasma membrane monoamine transporter (PMAT, Slc29a4)". Journal of Functional Foods. 54: 440–448. doi:10.1016/j.jff.2019.01.048. S2CID   91600074.
  21. ↑ Duan H, Hu T, Foti RS, Pan Y, Swaan PW, Wang J (November 2015). "Potent and Selective Inhibition of Plasma Membrane Monoamine Transporter by HIV Protease Inhibitors". Drug Metabolism and Disposition. 43 (11): 1773–1780. doi:10.1124/dmd.115.064824. PMC   4613949 . PMID   26285765. S2CID   1268101.


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