Plasma membrane monoamine transporter

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]

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; OMA:SLC29A4 - orthologs
Gene location (Human) Chr. Chromosome 7 (human)[5] Band 7p22.1 Start 5,274,369 bp[5] End 5,306,912 bp[5]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[6] Band 5|5 G2 Start 142,678,267 bp[6] End 142,708,245 bp[6]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in buccal mucosa cell islet of Langerhans hypothalamus internal globus pallidus ganglionic eminence anterior cingulate cortex right frontal lobe external globus pallidus substantia nigra lateral nuclear group of thalamus Top expressed in Epithelium of choroid plexus dentate gyrus of hippocampal formation granule cell neural tube facial motor nucleus cerebellar cortex ganglionic eminence ventricular zone external carotid artery primary visual cortex internal carotid artery More reference expression data BioGPS n/a
Gene ontology Molecular function monoamine transmembrane transporter activity nucleoside transmembrane transporter activity Cellular component integral component of membrane plasma membrane apical plasma membrane membrane Biological process nucleoside transmembrane transport monoamine transport transmembrane transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 V_max (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 K_m.^[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 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]

• Luteolin^[20]
• Cimetidine
• Decynium-22
• Dipyridamole
• Quinidine
• Quinine
• Tryptamine
• Verapamil
• Fluoxetine^[3]
• Sertraline^[3]
• Citalopram^[3]
• Fluvoxamine^[3]
• Paroxetine^[3]

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

Substrates

• Acetylcholine (poor)
• Adenosine (at low pH)
• Dopamine^[10]
• Epinephrine^[10]
• Histamine^[10] (poor)
• Metformin (poor, pH-dependent)
• MPP^+[10]
• Norepinephrine^[10]
• Serotonin^[10]
• Ritonavir^[12]

See also

• Extraneuronal monoamine transporter (EMT)

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. 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. 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. 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. GRCh38: Ensembl release 89: ENSG00000164638 – Ensembl, May 2017
6. 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. 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. 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. 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. 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. 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.