3 Clinical psychopharmacology3.3 Pharmacodynamics
3.3.1.8 Neurotransmitter transporters
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Written by Resident Doctor Committee · Published
New in the 2027 syllabus
The College added this topic for exams from January 2027.
What transporters do
A transporter is a membrane protein that moves a selected substance across a membrane by changing shape (conformation). Receptors mainly recognise signals. Transporters mainly move things.
Reuptake removes released transmitter from the extracellular fluid. It returns it to the presynaptic neurone or to nearby glia.
Sodium-coupled transport is powered by an ion gradient. This lets the transmitter move against its own concentration gradient.
The main transporters and drugs that act on them
Transporter | Location and action | Drugs that inhibit it |
|---|---|---|
Serotonin transporter (SERT) | Returns serotonin to the presynaptic terminal | Selective serotonin reuptake inhibitors |
Noradrenaline transporter (NET) | Returns noradrenaline to the terminal | Atomoxetine and serotonin-noradrenaline reuptake inhibitors |
Dopamine transporter (DAT) | Clears extracellular dopamine | Methylphenidate and cocaine |
Vesicular monoamine transporter 2 (VMAT2) | Loads monoamines into intracellular vesicles | Tetrabenazine |
Gamma-aminobutyric acid transporter 1 (GAT1) | Clears extracellular gamma-aminobutyric acid | Tiagabine |
How they are built and powered
SERT, NET and DAT belong to the SLC6 family. Each has twelve segments that cross the membrane. Their transport is coupled to sodium and chloride gradients.
Alternating access is how they work. The site that binds the substrate (the substance being carried) faces one side of the membrane, then the other. It is not a pore that stays open.
VMAT2 swaps protons out of the vesicle for monoamines coming in. A proton pump in the vesicle membrane builds the gradient that powers this.
Uptake across the cell membrane and storage in vesicles are separate steps. So blocking reuptake is not the same as stopping transmitter being packed into vesicles.
Blocking and reversing uptake
Reuptake inhibitors reduce clearance of transmitter. They do not need to act as agonists at the postsynaptic receptor.
Transporter substrates, such as amfetamine-type drugs, enter the terminal and promote monoamine release. Part of this is by making the transporter run in reverse.
Serotonin toxicity can follow when serotonergic mechanisms are combined, for example reuptake blockade plus a drug that stops monoamine breakdown.
P-glycoprotein is not a monoamine reuptake transporter. It is an ATP-dependent pump that pushes drugs out of cells at barriers such as the blood-brain barrier.