biology

Plasma membrane monoamine transporter

Plasma membrane monoamine transporter is a biology topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand Plasma membrane monoamine transporter rather than just read about it. In short: The plasma membrane monoamine transporter (PMAT) is a low-affinity monoamine transporter protein which in humans is encoded by the SLC29A4 gene. It is known alternatively as the human equilibrative nucleoside transporter-4 (hENT4).

Key takeaways

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Reference excerpt

The plasma membrane monoamine transporter (PMAT) is a low-affinity monoamine transporter protein which in humans is encoded by the SLC29A4 gene. It is known alternatively as the human equilibrative nucleoside transporter-4 (hENT4). It was discovered in 2004 and has been identified as a potential alternate target for treating various conditions.

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, from synaptic spaces into presynaptic neurons or neighboring glial cells. It is abundantly expressed in the human brain, heart tissue, and skeletal muscle, as well as in the kidneys, liver, and small intestine. 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, and has a significant impact on synaptic clearance of monoamines, especially under non-homeostatic conditions. 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. PMAT preferentially transports 5-HT and DA, with a transport efficiency comparable to SERT and DAT, but a with a lower Km. 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. 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. 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. In addition to transporting neurotransmitters at synapses, PMAT plays a key role in neurotoxin and drug removal from the cerebrospinal fluid. It is also likely to play a key role in histamine clearance from synapses, specifically through astrocytes.

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. It has several phosphorylation sites and a potential glycosylation site, and its first 6 transmembrane domains are suspected to be important for substrate recognition. 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. It was initially identified by a search of the draft human genome database through its sequence homology to ENTs (equilibrative nucleoside transporters).

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. Mice models with specific constitutive genetic deficiencies in PMAT have demonstrated behavioral changes relative to WT, including upon anti-depressant administration. 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. Parkinson's disease states may be affected by PMAT activity at the synapse, due to its higher affinity for dopamine. 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. 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.

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:

Luteolin Cimetidine Decynium-22 Dipyridamole Quinidine Quinine Tryptamine Verapamil Fluoxetine Sertraline Citalopram Fluvoxamine Paroxetine Lopinavir shows promising results as a newly discovered selective PMAT inhibitor that does not impact.

Substrates Acetylcholine (poor) Adenosine (at low pH) Dopamine Epinephrine Histamine (poor) Metformin (poor, pH-dependent) MPP+ Norepinephrine Serotonin Ritonavir

See also Extraneuronal monoamine transporter (EMT)

References

Illustrations

Worked examples

Example 1 — a first encounter with Plasma membrane monoamine transporter

Start with the simplest possible case. Write down what Plasma membrane monoamine transporter claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In biology, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Plasma membrane monoamine transporter before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Plasma membrane monoamine transporter ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Plasma membrane monoamine transporter

In research: Plasma membrane monoamine transporter appears in biology research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Plasma membrane monoamine transporter in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Plasma membrane monoamine transporter is common in secondary-school and first-year university syllabi. It links to neighbouring topics Genes on human chromosome 7, Membrane proteins, Molecular neuroscience, so understanding it makes those chapters shorter.
In everyday life: Look for Plasma membrane monoamine transporter outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

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Frequently asked questions

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