Adenosine transporters.

Abstract

1. In mammals, nucleoside transport is an important determinant of the pharmacokinetics, plasma and tissue concentration, disposition and in vivo biological activity of adenosine as well as nucleoside analogues used in antiviral and anticancer therapies. 2. Two broad types of adenosine transporter exist, facilitated-diffusion carriers and active processes driven by the transmembrane sodium gradient. 3. Facilitated-diffusion adenosine carriers may be sensitive (es) or insensitive (ei) to nanomolar concentrations of the transport inhibitor nitrobenzylthioinosine (NBMPR). Dipyridamole, dilazep and lidoflazine analogues are also more potent inhibitors of the es carrier than the ei transporter in cells other than those derived from rat tissues. 4. The es transporter has a broad substrate specificity (apparent Km for adenosine approximately 25 microM in many cells at 25 degrees C), is a glycoprotein with an average apparent Mr of 57,000 in human erythrocytes that has been purified to near homogeneity and may exist in situ as a dimer. However, there is increasing evidence to suggest the presence of isoforms of the es transporter in different cells and species, based on kinetic and molecular properties. 5. The ei transporter also has a broad substrate specificity with a lower affinity for some nucleoside permeants than the es carrier, is genetically distinct from es but little information exists as to the molecular properties of the protein. 6. Sodium-dependent adenosine transport is present in many cell types and catalysed by four distinct systems, N1-N4, distinguished by substrate specificity, sodium coupling and tissue distribution. 7. Two genes have been identified which encode sodium-dependent adenosine transport proteins, SNST1 from the sodium/glucose cotransporter (SGLT1) gene family and the rat intestinal N2 transporter (cNT1) from a novel gene family including a bacterial nucleoside carrier (NupC). Transcripts of cNT1, which encodes a 648-residue protein, are found in intestine and kidney only. 8. Success in cloning the remaining adenosine transporter genes will improve our understanding of the diversity of nucleoside transport processes, with a view to better targeting of therapeutic nucleoside analogues and protective use of transport inhibitors.