Peptide transporters in the brain: Role of PEPT2 in choroid plexus.

Abstract

Peptide transporters have become increasingly important in drug design and phamacokinetic analysis over the past 10 years. These transporters are involved in the handling of small peptide fragments and peptidomimetics from absorption to elimination. Because of differential tissue expression, specificity and capacity these transporters may be manipulated for tissue specific delivery of peptidomimetics. Recently, the renal peptide transporter PEPT2 was cloned from rat brain homogenate, and PEPT2 mRNA was localized in the choroid plexus. The choroid plexus acts as the barrier between the plama and the cerebrospinal fluid (CSF). These initial findings have led us to examine the function of PEPT2 in choroid plexus. Using whole tissue choroid plexus and primary cell cultures, I evaluated the presence, function and specificity of PEPT2 in rat choroid plexus epithelial cells. I demonstrated that PEPT2 is functionally active in choroid plexus tissue, has affinity for many neuropeptides, is located on the apical membrane of the choroidal epithelium, and is involved in neuropeptide homeostasis at the blood-CSF barrier. In addition, I discovered another transporter in choroidal epithelium that appears to transport peptides and organic compounds. This transporter, in conjuction with PEPT2, serves to clear neuropeptides from the CSF. The results of this research have provided a fundamental base for future research regarding PEPT2 in the brain. By demonstrating the presence of PEPT2 in choroid plexus, its affinity for endogenous compounds, and the directionality of transport, we have provided important information regarding the physiologic function and potential pharmaceutical role of PEPT2. These results could have great impact in pharmaceutical drug development, design, distribution, and tissue targeting.