Who Is Who in Adenosine Transport.

Extracellular adenosine concentrations are regulated by a panel of membrane transporters which, in most cases, mediate its uptake into cells. Adenosine transporters belong to two gene families encoding Equilibrative and Concentrative Nucleoside Transporter proteins (ENTs and CNTs, respectively). The lack of appropriate pharmacological tools targeting every transporter subtype has introduced some bias on the current knowledge of the role of these transporters in modulating adenosine levels. In this regard, ENT1, for which pharmacology is relatively well-developed, has often been identified as a major player in purinergic signaling. Nevertheless, other transporters such as CNT2 and CNT3 can also contribute to purinergic modulation based on their high affinity for adenosine and concentrative capacity. Moreover, both transporter proteins have also been shown to be under purinergic regulation via P1 receptors in different cell types, which further supports its relevance in purinergic signaling. Thus, several transporter proteins regulate extracellular adenosine levels. Moreover, CNT and ENT proteins are differentially expressed in tissues but also in particular cell types. Accordingly, transporter-mediated fine tuning of adenosine levels is cell and tissue specific. Future developments focusing on CNT pharmacology are needed to unveil transporter subtype-specific events.