Plasma membrane monoamine transporter
The plasma membrane monoamine transporter (PMAT) is a low-affinity
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| Location (UCSC) | Chr 7: 5.27 – 5.31 Mb | Chr 5: 142.68 – 142.71 Mb | |||||||
| PubMed search | [7] | [8] | |||||||
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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,
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.
Clinical significance
Common
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
- S2CID 8817821.
- ^ S2CID 26542965.
- ^ PMID 19022290.
- ^ PMID 28018168.
- ^ a b c GRCh38: Ensembl release 89: ENSG00000164638 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000050822 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 19357181.
- ^ PMID 28768996.
- PMID 17408864.
- ^ PMID 27317943.
- PMID 25615632.
- ^ PMID 36316031.
- ^ PMID 27506881.
- PMID 20592246.
- ^ PMID 15448143.
- PMID 35954298.
- PMID 34194474.
- S2CID 91600074.
- S2CID 1268101.
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