Serotonin transporter (SERT), dopamine transporter (DAT), and norepinephrine transporter (NET) (MATs)

The serotonin, dopamine, and norepinephrine transporters (SERT, DAT, and NET) are integral membrane proteins belonging to the solute carrier family 6 (SLC6) that regulate the intensity and duration of monoaminergic signaling [UniProt]. These transporters are responsible for the high-affinity reuptake of their respective neurotransmitters from the synaptic cleft back into the presynaptic terminals, effectively terminating the signal and recycling the neurotransmitters for future use [StatPearls, 2023]. Dysregulation of these transport systems is central to the pathophysiology of various neuropsychiatric and neurological conditions, including major depressive disorder, ADHD, and Parkinson's disease [NCBI, 2021]. Pharmacological modulation of these transporters is a cornerstone of modern psychiatry; drugs may target them individually (e.g., SSRIs), in pairs (e.g., SNRIs), or collectively as triple reuptake inhibitors (TRIs) [PubMed, 2022]. While increasing synaptic monoamine levels can alleviate symptoms of depression and improve focus, targeting these transporters—particularly DAT—carries risks of cardiovascular side effects and potential for substance abuse [StatPearls, 2023]. Understanding the specific binding profiles and occupancy levels of these transporters is crucial for developing effective therapies with manageable side effect profiles.

Other names

Monoamine transportersSERT, DAT, and NETSLC6A4, SLC6A3, and SLC6A2Biogenic amine transportersSodium-dependent monoamine transporters

Drugs targeting these transporters primarily act as reuptake inhibitors, binding to the transporter protein to prevent the translocation of neurotransmitters from the extracellular space back into the presynaptic neuron [StatPearls, 2023]. Some agents, such as amphetamines, act as substrates that enter the neuron and trigger a phosphorylation-dependent reversal of the transporter, leading to the non-exocytotic release of neurotransmitters into the synapse [NCBI, 2021].