Norepinephrine transporter (NET) (NET)

The Norepinephrine Transporter (NET), encoded by the SLC6A2 gene, is a transmembrane protein primarily responsible for the sodium- and chloride-dependent reuptake of norepinephrine (NE) from the synaptic cleft back into presynaptic neurons (UniProt P23975). This process is the major mechanism for terminating noradrenergic signaling in both the central and peripheral nervous systems, thereby regulating physiological processes such as attention, mood, and autonomic cardiovascular control (StatPearls: Norepinephrine). Beyond simple reuptake inhibition, certain drugs act as substrates for NET, entering the neuron and promoting the release of NE from cytoplasmic pools and vesicular stores into the synapse via a process called reverse transport (PubMed: 15955514). This redistribution of cytoplasmic norepinephrine is a hallmark of indirect sympathomimetic agents like amphetamines. Clinically, NET is a major target for antidepressants, such as SNRIs and TCAs, and treatments for Attention Deficit Hyperactivity Disorder (ADHD), such as atomoxetine. Dysfunction or genetic variants of NET are associated with orthostatic intolerance and various psychiatric conditions. Monitoring NET activity often involves neuroimaging with radioligands or measuring norepinephrine metabolites like MHPG in biological fluids (PubMed: 21945130).

Other names

Solute carrier family 6 member 2SLC6A2Sodium-dependent noradrenaline transporterNAT1NET1

Inhibition of the sodium-dependent reuptake of norepinephrine from the synaptic cleft into the presynaptic terminal; additionally, certain agents act as substrates that induce the efflux of norepinephrine from cytoplasmic pools into the synapse via reverse transport.