Norepinephrine transporter (SLC6A2) (NET)

The Norepinephrine transporter (NET), encoded by the SLC6A2 gene, is a sodium-dependent transmembrane protein responsible for the reuptake of norepinephrine from the synaptic cleft into presynaptic neurons (UniProt P23975). This process is the primary mechanism for terminating noradrenergic signaling in both the central and peripheral nervous systems, thereby regulating physiological processes such as heart rate, blood pressure, and cognitive functions like attention and arousal. NET is a significant therapeutic target for various conditions, including attention-deficit/hyperactivity disorder (ADHD), major depressive disorder, and obesity. Phenmetrazine, the active metabolite of the anorectic prodrug phendimetrazine, acts as a potent norepinephrine-releasing agent by serving as a substrate for NET (StatPearls, 2023). This interaction reverses the direction of the transporter, leading to an efflux of norepinephrine into the synapse, which contributes to its stimulant and appetite-suppressant effects (Rothman et al., 2003). Because of its influence on the sympathetic nervous system, pharmacological modulation of NET is associated with cardiovascular side effects such as tachycardia and hypertension. Furthermore, drugs that induce neurotransmitter release through NET often carry a risk for abuse and dependence due to their stimulant properties (PubMed). Dysregulation of NET function is also linked to autonomic disorders like postural orthostatic tachycardia syndrome (POTS).

Other names

Solute carrier family 6 member 2Sodium-dependent noradrenaline transporterSLC6A2NAT1NET1

Substrate-mediated release and reuptake inhibition of norepinephrine via the transporter.