Biology:Plasma membrane monoamine transporter

From HandWiki
Short description: Protein-coding gene in the species Homo sapiens

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]

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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,[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.[12] 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.[12] 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.[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.[13] 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.

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][14] 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.[12] 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

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.[12][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.[16] 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.[16]

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.[17][8]

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

Substrates

See also

  • Extraneuronal monoamine transporter (EMT)

References

  1. ↑ "The equilibrative nucleoside transporter family, SLC29". Pflugers Archiv 447 (5): 735–743. February 2004. doi:10.1007/s00424-003-1103-2. PMID 12838422. 
  2. ↑ 2.0 2.1 "Interaction of organic cations with a newly identified plasma membrane monoamine transporter". Molecular Pharmacology 68 (5): 1397–1407. November 2005. doi:10.1124/mol.105.016832. PMID 16099839. 
  3. ↑ "Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for antidepressant efficacy". Pharmacology & Therapeutics 121 (1): 89–99. January 2009. doi:10.1016/j.pharmthera.2008.10.004. PMID 19022290. 
  4. ↑ "What Mechanisms Are Responsible for the Reuptake of Levodopa-Derived Dopamine in Parkinsonian Striatum?". Frontiers in Neuroscience 10: 575. 2016. doi:10.3389/fnins.2016.00575. PMID 28018168. 
  5. ↑ "Podocyte-specific expression of organic cation transporter PMAT: implication in puromycin aminonucleoside nephrotoxicity". American Journal of Physiology. Renal Physiology 296 (6): F1307–F1313. June 2009. doi:10.1152/ajprenal.00046.2009. PMID 19357181. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 "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. 2017. doi:10.1248/bpb.b17-00076. PMID 28768996. 
  7. ↑ "Expression and immunolocalization of the plasma membrane monoamine transporter in the brain". Neuroscience 146 (3): 1193–1211. May 2007. doi:10.1016/j.neuroscience.2007.01.072. PMID 17408864. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 "Polyspecific organic cation transporters and their impact on drug intracellular levels and pharmacodynamics". Pharmacological Research 111: 237–246. September 2016. doi:10.1016/j.phrs.2016.06.002. PMID 27317943. 
  9. ↑ "Serotonylation and Transamidation of Other Monoamines". ACS Chemical Neuroscience 6 (7): 961–969. July 2015. doi:10.1021/cn500329r. PMID 25615632. 
  10. ↑ 10.0 10.1 10.2 10.3 "Summarizing studies using constitutive genetic deficiency to investigate behavioural influences of uptake 2 monoamine transporters". Basic & Clinical Pharmacology & Toxicology 133 (5): 439–458. November 2023. doi:10.1111/bcpt.13810. PMID 36316031. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 "The plasma membrane monoamine transporter (PMAT): Structure, function, and role in organic cation disposition". Clinical Pharmacology and Therapeutics 100 (5): 489–499. November 2016. doi:10.1002/cpt.442. PMID 27506881. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 12.7 12.8 "Unfaithful neurotransmitter transporters: focus on serotonin uptake and implications for antidepressant efficacy". Pharmacology & Therapeutics 121 (1): 89–99. January 2009. doi:10.1016/j.pharmthera.2008.10.004. PMID 19022290. 
  13. ↑ "Adenosine transport by plasma membrane monoamine transporter: reinvestigation and comparison with organic cations". Drug Metabolism and Disposition 38 (10): 1798–1805. October 2010. doi:10.1124/dmd.110.032987. PMID 20592246. 
  14. ↑ 14.0 14.1 "Identification and characterization of a novel monoamine transporter in the human brain". The Journal of Biological Chemistry 279 (48): 50042–50049. November 2004. doi:10.1074/jbc.M407913200. PMID 15448143. 
  15. ↑ "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. August 2022. doi:10.3390/cells11152454. PMID 35954298. 
  16. ↑ 16.0 16.1 "What Mechanisms Are Responsible for the Reuptake of Levodopa-Derived Dopamine in Parkinsonian Striatum?". Frontiers in Neuroscience 10: 575. 2016. doi:10.3389/fnins.2016.00575. PMID 28018168. 
  17. ↑ "The Genetics of Adverse Drug Outcomes in Type 2 Diabetes: A Systematic Review". Frontiers in Genetics 12: 675053. 2021-06-14. doi:10.3389/fgene.2021.675053. PMID 34194474. 
  18. ↑ "Luteolin shows antidepressant-like effect by inhibiting and downregulating plasma membrane monoamine transporter (PMAT, Slc29a4)". Journal of Functional Foods 54: 440–448. March 2019. doi:10.1016/j.jff.2019.01.048. 
  19. ↑ "Potent and Selective Inhibition of Plasma Membrane Monoamine Transporter by HIV Protease Inhibitors". Drug Metabolism and Disposition 43 (11): 1773–1780. November 2015. doi:10.1124/dmd.115.064824. PMID 26285765. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Plasma_membrane_monoamine_transporter&oldid=3689364"