The ability of the neurotransmitter transporters to regulate normal synaptic signaling implies that functional modification of transporter activity might contribute to the etiology of multiple neurobiological diseases. Indeed, many studies have suggested for years, largely on the basis of pharmacology, that the monoamine transporters NET, DAT, and SERT play an important role in regulating mood, learning, and motor activity, while GABA transporters have been implicated in neuronal excitability dysfunction such as epilepsy. Indeed, a decade of innovative pharmacology resulted in the development of compounds that, by targeting neurotransmitter transporters, alleviate the symptoms of neurological diseases such as drug abuse and attention deficit/hyperactivity disorder. New hopes for the cure of these conditions are coming from studying the gene organization and polymorphisms of these membrane proteins. It has been shown that variations in the human neurotransmitter transporter sequences, known as polymorphisms, may alter transporter expression level, activity, or regulation that ultimately may influence the levels of extracellular neurotransmitter. The cloning of the neurotransmitter transporter genes has provided the tool for examining transporter genetic variations and possibly to correlate them to human diseases. This is particularly true for the monoamine transporters (SERT, DAT, NET) each encoded by a single gene. Therefore, the impact of polymorphisms could have far-reaching consequences due to a limited opportunity for compensation from other genes. Finding an association of a polymorphism with disease is clearly the first of many steps toward understanding how genetics shape the neurobiological diseases. A recent example of such an effort is the identification of a NET coding variant, A457P, in subjects with orthostatic intolerance.
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