Ectonucleotidases and nucleotide/nucleoside transporters as pharmacological targets for neurological disorders

Extracellular nucleotide and nucleoside are signaling molecules with a wide range of actions in the central nervous system (CNS). Extracellular ATP is released by several mechanisms involving ATP binding cassette transporters, hemichannels, P2X7 receptors, or volume-sensitive chloride channels. The levels of ATP and its hydrolysis product, adenosine, in the synaptic cleft are controlled by a complex cascade of cell surface-located enzymes collectively known as ectonucleotidases. There are four major families of ectonucleotidases: ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases), ecto-nucleotide pyrophosphatase/phosphodiesterases (E-NPPs), alkaline phosphatases, and ecto-5'- nucleotidase. Besides the production of adenosine through nucleotide hydrolysis, this neuromodulator can be released as adenosine per se by equilibrative and/or concentrative nucleoside transporters. In this review, the involvement of nucleotide/nucleoside transporters and ectonucleotidases in the pathophysiology of brain disorders is discussed. The identification of compounds able to modulate the activity of these players in purinergic neurotransmission and their implications in neurological disorders as potential targets for drug discovery is also highlighted.