Regulation of Monoamine Transporters

Abstract

The monoamines that include dopamine (DA), norepinephrine (NE), and serotonin (5-hydroxytryptamine, 5-HT) act as neurotransmitters in peripheral and central nervous systems (CNS) in a variety of physiological (cognitive, autonomic, and emotional) functions (1–6). Synaptic neu-rotransmission in the central nervous system requires the precise control of the duration and the magnitude of neurotransmitter action at specific molecular targets (7–9). At the molecular level, neurotransmitter signaling is dynamically regulated by a diverse set of macromolecules, including biosynthetic enzymes, secretory proteins, ion channels, pre- and postsynaptic receptors and transporters. The catecholamines DA and NE, which are derived from tyrosine, and the indolamine 5-HT, which is derived from tryptophan, are packaged into synaptic vesicles and released into synapses in response to depolarizing stimuli to activate pre-and postsynaptic receptors and elicit synaptic responses. Monoamine transporters localized near sites of neurotransmitter release remove transmitters from the synaptic cleft and its vicinity, and transport them back into presynaptic neurons. Monoamine transporters belong to the Na+, Cl−-dependent, gamma-amino butyric acid (GABA)/norepinephrine transporter (GAT1/NET) gene family, which also includes transporters for proline (PROT), taurine (TauT), glycine (GLYT), creatine (CreaT), betaine (BGT), and other “orphan” transporters (10–12). Monoamine transporters are the sites of action for widely used antidepressant drugs and are also high-affinity molecular targets for drugs of abuse including cocaine, amphetamine, and (+)−3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”) (13-15) (see also Chapter 3).