Molecular characterization of neurotransmitter transporters

Rapid chemical signaling between neurons and target cells is dependent upon the precise control of the concentration and duration of neurotransmitters in synaptic spaces. After transmitter release from activated nerve terminals, the principal mechanism involved in the rapid clearance from the synapse of the biogenic amine and amino acid neurotransmitters is active transport of the transmitter back into presynaptic nerve terminals or glial surrounding cells by one of a large number of specific, pharmacologically distinguishable membrane transport proteins (1). High affinity, Na+-dependent uptake activities, analogous to the noradrenergic carrier first described at peripheral synapses by Axelrod and colleagues (2) have been identified in mammalian central nervous system (CNS) nerve terminals for the biogenie amine neurotransmitters including norepinephrine (NE), dopamine (DA), and serotonin (5HT) for the excitatory amino acid neurotransmitters L-glutamate and L-aspartate, and for the inhibitory amino acid neurotransmitters r-amino butyric acid (GABA) and glycine (3). The primary function of plasma membrane neurotransmitter transporters is to clear the synapse of the neurotransmitter between nerve impulses and to replenish neurotransmitter levels in presynaptic nerve terminals. In certain cases, Na+-dependent transport processes may also mediate the presynaptic accumulation of neurotransmitter precursors as well. For example, the rate-limiting step in the biosynthesis of acetylcholine appears to be Na+dependent choline uptake into cholinergic nerve terminals by a hemicholiniumsensitive high affinity choline transporter (5). Neurotransmitter transporters represent critical targets for therapeutic and pathological alterations of synaptic function. This is particularly apparent with the tricyclic antidepressants, amphetamines, and cocaine, agents that block biogenic amine transport and produce dramatic behavioral changes (6). Abnormalities of neurotransmitter transport can contribute to neuropathol-