MOLECULAR PHYSIOLOGY OF NOREPINEPHRINE AND SEROTONIN TRANSPORTERS

Cocaine- and antidepressant-sensitive norepinephrine and serotonin tra nsporters (NETs and SERTs) are closely related members of the Na+/Cl- transporter gene family, whose other members include transporters for inhibitory amino acid transmitters, neuromodulators, osmolytes and nut rients. Availability of cloned NET and SERT cDNAs has permitted rapid progress in the definition of cellular sites of gene expression, the g eneration of transporter-specific antibodies suitable for biosynthetic and localization studies, the examination of structure-function relat ionships in heterologous expression systems and a biophysical analysis of transporter function. In situ hybridization and immunocytochemical studies indicate a primary expression of NET and SERT genes in brain by noradrenergic and serotonergic neurons, respectively. Both NET and SERT are synthesized as glycoproteins, with multiple glycosylation sta tes apparent for SERT proteins in the brain and periphery. N-glycosyla tion of NET and SERT appears to be essential for transporter assembly and surface expression, but not for antagonist binding affinity. Homol ogy cloning efforts have revealed novel NET and SERT homologous in non mammalian species that are of potential value in the delineation of th e precise sites for substrate and antagonist recognition, including a Drosophila melanogaster SERT with NET-like pharmacology. Electrophysio logical recording of human NETs and SERTs stably expressed in HEK-293 cells reveals that both transporters move charge across the plasma mem brane following the addition of substrates; these currents can be bloc ked by NET- and SERT-selective antagonists as well as by cocaine.