Nucleosides play other important roles beyond their nucleic acid synthesis building block role. For example, they are involved in energy metabolism; they serve as ligands of purinergic receptors and act as influential signaling molecules¹. Being hydrophilic, nucleosides cannot simply diffuse across the plasma membrane in order to exert their various functions, but rather need to be physically transported via nucleoside transporters^1,2.

Two different transporter families are responsible for transporting nucleosides across the plasma membrane: the Concentrative nucleoside transporter proteins (CNT, SLC28 family), which consist of three members, CNT1-3, and act as Na⁺-dependent symporters^1,3 and the Equilibrative nucleoside transporter proteins ENT1-4 (ENT, SLC29 family), which mediate a Na⁺-independent facilitated diffusion. Therefore, ENTs act as bidirectional carriers, responsible for the influx and efflux of substrates¹.

CNTs are responsible for the intracellular uptake of nucleosides, an energy consuming process which is coupled to the Na⁺ gradient across the plasma membrane. All three transporters display a relatively high affinity for their substrates but a more selective than ENTs^1,4. Pyrimidines are the substrate of choice for CNT1 although it can bind but not transport adenosine. CNT2 prefers purines, although it can transport uridine, and CNT3 is selective for both types of nucleosides. Both CNT1 and CNT2 display a 1:1 stoichiometry (nucleoside:sodium)^1,5. CNT3 on the other hand transports two Na⁺ ions per nucleoside, and can also co-transport protons in a pH dependent manner in a 1:1 ratio^1,6,7.

All three CNTs have thirteen transmembrane domains and an extracellular C-terminus responsible for substrate recognition¹.

CNT1 is widely expressed in the small intestine, kidney and liver^1,8-10. CNT2 is expressed in immune system cells^1,8 and CNT3 expression is abundant in monocytes and macrophages. All three are detected in various regions of the brain^1,6,11,12.

There is no evidence that nucleoside transporters are directly involved in pathophysiologies, but they are clinically significant. For example, nucleoside transporters are responsible for the cellular uptake of a number of nucleoside-derived anticancer drugs¹.