The norepinephrine transporter and regulation of synaptic transmission

Introduction Norepinephrine (NE) signaling involves a coordinated function of a variety of biosynthetic enzymes, ion channels, and pre- and postsynaptic receptors. The action of NE after release is terminated via a reuptake process into a presynaptic site, a process referred to as “neuronal reuptake” or “uptake-1”. Neuronal reuptake involves the transfer of NE across the neuronal membrane. Julius Axelrod discovered the existence of the neuronal reuptake process, and provided evidence documenting this process as the primary mechanism for the efficient clearance of NE from the extracellular space. It is now well established that neuronal reuptake is mediated by the neuronal plasma membrane resident transporter protein, the norepinephrine transporter (NET). Nonneuronal cells take up NE via uptake-2, an alternative mechanism for the inactivation of NE. This process is mediated by distinct transporter molecules, including OCT-1, OCT-2, and EMT. Nonneuronal uptake primarily clears circulating catecholamines, rather than neuronal NE. Uptake-2 may contribute to the clearance of synaptic NE under conditions of diminished NET function. The NET is of prime interest because it is a molecular target for many antidepressants, including the tricyclics, and commonly abused substances, including cocaine and amphetamines. The recent identification of a coding mutation in the NET gene resulting in compromised NET function, the existence of genetic variants, and the emergence of newer NET-specific inhibitors of clinical significance (reboxetine and atomoxetine) have stimulated new interest in understanding the function and regulation of NETs in physiological and pathophysiological states.