NEUROTRANSMITTER REUPTAKE MECHANISMS - TARGETS FOR DRUGS TO STUDY AND TREAT PSYCHIATRIC, NEUROLOGICAL AND NEURODEGENERATIVE DISORDERS

In the last 5 years, there has been considerable progress in the molecular characterisation of multiple neurotransmitter reuptake mechanisms (or neurotransporters). Neurotransporters an high affinity reuptake proteins located in the plasma membrane of both presynaptic nerve and glial cells, They mediate the removal of the neurotransmitter from the synaptic cleft or represent intracellular transport systems that concentrate neurotransmitters in synaptic vesicles. Based on subcellular distribution and pharmacological properties, neurotransporters have been placed into 3 main subgroups: (i) Na+/Cl--or (ii) Na+/K+-dependent cell surface transporters, and (iii) H+-dependent transporters associated with synaptic vesicles, The new insights into neurotransporter diversity provide the means for novel approaches of studying reuptake processes at the molecular level, Current research strategies are focusing on functional mechanisms of substrate translocation and antagonist binding. as well as on molecular regulation of neurotransporter gene expression and on post-translational modification at the neurotransporter protein level. Interesting information will also be derived from the analysis of genomic regulatory elements, as well as from modelling neurotransporter-related disorders and novel therapeutic strategies in genetically engineered animals, Through an improved understanding of the modulation of the function of neurotransporters in the brain. it may be possible to identify the molecular factors underlying both the predisposition to, and the pathogenesis of psychiatric, neurological and neurodegenerative disorders. Neurotransporters have long been regarded as primary sites of action for tri- and heterocyclic antidepressant drugs in the treatment of a variety of neuropsychiatric conditions. Nevertheless, due to their increasingly appreciated heterogeneity, as well as their specificity for distinct neuronal systems, we are currently witnessing a renaissance of various neurotransmitter reuptake mechanisms as potential targets for novel therapeutic strategies.