Theplasma membrane monoamine transporter (PMAT) is a low-affinitymonoamine transporterprotein which in humans is encoded by theSLC29A4gene.[1] It is known alternatively as thehuman 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]
The plasma membrane monoamine transporter is an integral membrane protein that transports the monoamine neurotransmitters (serotonin,dopamine,norepinephrine) as well asadenosine,[9] from synaptic spaces into presynaptic neurons or neighboringglial 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 naturallynegative 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 atransport efficiency comparable to SERT and DAT, but a with a lower Km.[3] PMAT and similar transporters likeOCT3 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 underischemic conditions) its transport efficiency increases for all substrates, whereas at high pH (>8) transport is blocked.[12][15] Unlike other members of theENT family, it is impermeable to mostnucleosides, with the exception of the inhibitory neurotransmitter andribonucleosideadenosine, 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 thecerebrospinal 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 SLC22AOCT 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]
CommonSSRIs 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 inhibitorDecynium-22, suggesting a tentative mechanism fortreatment-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 ofGI disturbance side effects withmetformin administration, the most common type II diabetes medication.[19][12]
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 ofdecynium-22, which is more potent. These compounds include:[2]
^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.PMID12838422.S2CID8817821.
^abEngel 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.PMID16099839.S2CID26542965.
^Muma NA, Mi Z (July 2015). "Serotonylation and Transamidation of Other Monoamines".ACS Chemical Neuroscience.6 (7):961–969.doi:10.1021/cn500329r.PMID25615632.
