Directed Mutagenesis in Structure Activity Studies of Neurotransmitter Transporters

Abstract

The delicate balance between excitation and inhibition within the central nervous system is critical to the maintenance of normal brain function. Players key to this balance are neurotransmitter transporters. Neurotransmitter transporters are drawn from two families of solute carriers (SLC), SLC1 and SLC6. The transporters for glutamate and small neutral amino acids belong to the SLC1 family, while transport of monoamines (5hydroxytryptamine, dopamine, noradrenaline) and amino acid neurotransmitters (γaminobutyric acid, glycine) are mediated by members of the SLC6 family. These integral membrane proteins regulate the concentration of neurotransmitters, such as glutamate and glycine, within the synapse. They utilise pre-existing electrochemical gradients to drive the transport of neurotransmitters across neuronal and glial membranes, terminating neurotransmission and replenishing intracellular levels of neurotransmitter for future release. Neurotransmitter transporters are targeted by a number of substances, both therapeutic (antidepressants, anticonvulsant, antipsychotics, analgesics, anxiolytics) and addictive (cocaine, methampetamine). Their dysfunction is associated with multiple disorders, including epilepsy, ischaemic stroke, neuropathic pain and schizophrenia (Dohi et al., 2009; Sur & Kinney, 2004). Thus, structure activity studies of transporters are essential to provide new insights into their function and direct the design of novel, transporterspecific therapeutics.