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User:Johnskad/Plasma membrane monoamine transporter

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Copied from 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). 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.

This protein is an integral membrane protein that transports the monoamine neurotransmitters (serotonin, dopamine, norepinephrine) as well as adenosine,[2] from synaptic spaces into presynaptic neurons or neighboring glial cells. It is abundantly expressed in the human brain,[3] heart tissue, and skeletal muscle, as well as in the kidneys. 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. Its transport of monoamines, unlike for adenosine, is pH-insensitive. At low pH, (5.5-6.5 range, as occurs under ischemic conditions) however, its transport efficiency for adenosine becomes greater than for serotonin.

It has 530 amino acid residues with 10–12 transmembrane segments, and is not homologous to other known monoamine transporters, such as the high-affinity SERT, DAT, and NET, or the low-affinity SLC22A OCT family. It was initially identified by a search of the draft human genome database through its sequence homology to ENTs (equilibrative nucleoside transporters).[4]

Ligands

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Inhibitors

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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:[5]

Substrates

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See also

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References

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  1. ^ Baldwin SA, Beal PR, Yao SY, King AE, Cass CE, Young JD (February 2004). "The equilibrative nucleoside transporter family, SLC29". Pflugers Archiv. 447 (5): 735–743. doi:10.1007/s00424-003-1103-2. PMID 12838422. S2CID 8817821.
  2. ^ 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.
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.


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Article Draft

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Lead

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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]

Article body

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Structure and Function

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Transport function: This protein is an integral membrane protein that transports the monoamine neurotransmitters (serotonin, dopamine, norepinephrine) as well as adenosine,[5] from synaptic spaces into presynaptic neurons or neighboring glial cells[6]. It is abundantly expressed in the human brain,[7] heart tissue, and skeletal muscle, as well as in the kidneys, liver, and small intestine[8]. 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,[9]and has a significant impact on synaptic clearance of monoamines, especially under non-homeostatic conditions.[6][10] 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.[8] [11]

PMAT preferentially transports 5-HT and DA[10], 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] Its transport of monoamines, unlike for adenosine, is pH-insensitive (pH sensitivity reference here). At low pH, (5.5-6.5 range, as occurs under ischemic conditions) however, its transport efficiency for adenosine becomes greater than for serotonin. At low 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.[8][11] 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[12]. In addition to transporting neurotransmitters at synapses, PMAT plays a key role in neurotoxin and drug removal from the cerebrospinal fluid.[11] It is also likely to play a key role in histamine clearance from synapses, specifically through astrocytes. [6]

PMAT's proposed structure.

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.[11][8][13] It has several phosphorylation sites and a potential glycosylation site, and its first 6 transmembrane domains are suspected to be important for substrate recognition.[11] 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).[14]

Clinical Significance

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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][10] Mice models with specific constitutive genetic deficiencies in PMAT have demonstrated behavioral changes relative to WT, including upon anti-depressant administration.[10] 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.[15]

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.[16][8]

Ligands

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Inhibitors

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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:[17]

Lopinavir[6] shows promising results as a newly discovered selective PMAT inhibitor that does not impact.[19]

Substrates

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References

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  1. ^ Baldwin SA, Beal PR, Yao SY, King AE, Cass CE, Young JD (February 2004). "The equilibrative nucleoside transporter family, SLC29". Pflugers Archiv. 447 (5): 735–743. doi:10.1007/s00424-003-1103-2. PMID 12838422. S2CID 8817821.
  2. ^ Engel, Karen; Zhou, Mingyan; Wang, Joanne (2004-11). "Identification and Characterization of a Novel Monoamine Transporter in the Human Brain". Journal of Biological Chemistry. 279 (48): 50042–50049. doi:10.1074/jbc.M407913200. {{cite journal}}: Check date values in: |date= (help)CS1 maint: unflagged free DOI (link)
  3. ^ a b c d e f g h i j Daws, Lynette C. (2009-01-01). "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. ISSN 0163-7258.
  4. ^ a b c Nishijima, Haruo; Tomiyama, Masahiko (2016). "What Mechanisms Are Responsible for the Reuptake of Levodopa-Derived Dopamine in Parkinsonian Striatum?". Frontiers in Neuroscience. 10. doi:10.3389/fnins.2016.00575/full. ISSN 1662-453X.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ 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.
  6. ^ a b c d e f g h i j Furihata, Tomomi; Anzai, Naohiko (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 and Pharmaceutical Bulletin. 40 (8): 1153–1160. doi:10.1248/bpb.b17-00076.
  7. ^ 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.
  8. ^ a b c d e f Wagner, David J.; Hu, Tao; Wang, Joanne (2016-09). "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. {{cite journal}}: Check date values in: |date= (help)
  9. ^ Muma, Nancy A.; Mi, Zhen (2015-07-15). "Serotonylation and Transamidation of Other Monoamines". ACS Chemical Neuroscience. 6 (7): 961–969. doi:10.1021/cn500329r. ISSN 1948-7193.
  10. ^ a b c d Weber, Brady L.; Beaver, Jasmin N.; Gilman, T. Lee (2022-11-20). "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. ISSN 1742-7835.
  11. ^ a b c d e Wang, J (2016-11). "The plasma membrane monoamine transporter (PMAT): Structure, function, and role in organic cation disposition". Clinical Pharmacology & Therapeutics. 100 (5): 489–499. doi:10.1002/cpt.442. ISSN 0009-9236. {{cite journal}}: Check date values in: |date= (help)
  12. ^ Zhou, Mingyan; Duan, Haichuan; Engel, Karen; Xia, Li; Wang, Joanne (2010-10). "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. ISSN 0090-9556. PMC 2957165. PMID 20592246. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  13. ^ Cite error: The named reference :6 was invoked but never defined (see the help page).
  14. ^ 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.
  15. ^ Bowman, Melodi A.; Gomez, Jorge A.; Mitchell, Nathan C.; Wells, Anne M.; Vitela, Melissa; Clarke, Kyra M.; Horton, Rebecca E.; Koek, Wouter; Daws, Lynette C. (2022-08-08). "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. ISSN 2073-4409.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  16. ^ Baye, Assefa M.; Fanta, Teferi G.; Siddiqui, Moneeza K.; Dawed, Adem Y. (2021-06-14). "The Genetics of Adverse Drug Outcomes in Type 2 Diabetes: A Systematic Review". Frontiers in Genetics. 12. doi:10.3389/fgene.2021.675053. ISSN 1664-8021.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  17. ^ 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.
  18. ^ 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.
  19. ^ Duan, Haichuan; Hu, Tao; Foti, Robert S.; Pan, Yongmei; Swaan, Peter W.; Wang, Joanne (2015-08-18). "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. ISSN 0090-9556.
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