2.A.22.1.2
Noradrenaline (norepinephrine):Na⁺ symporter (NET1, NAT1, SLC6A2) (also transports 1-methyl-4-tetrahydropyridinium and amphetamines; it is a target of cocaine and amphetamines as well as of therapetics for depression, obsessive-compulsive disorders, and post-traumatic stress disorder. This homooligomeric transporter binds one substrate molecule per transporter subunit (Schwartz et al., 2005; Schlessinger et al., 2011; Andersen et al., 2011). Extracellular loop 3 contributes to substrate and inhibitor selectivity (Lynagh et al. 2013). The highly conserved MELAL and GQXXRXG motifs, located in the second transmembrane domain and the first intracellular loop of hNET, respectively, are determinants of NET cell surface expression, and substrate and inhibitor binding (Sucic and Bryan-Lluka 2007). Based on modeling, the high affinity substrate binding site (S1) of the human norepinephrine transporter has been predicted and then verified by mutational studies (Jha et al. 2020). Proline residues play roles in the expression and function of the human noradrenaline transporter (Paczkowski and Bryan-Lluka 2004). Phosphatidylinositol 4,5-bisphosphate (PIP₂) facilitates norepinephrine transporter dimerization and modulates substrate efflux (Luethi et al. 2022).