Targeted disruption of the PEPT2 gene markedly reduces dipeptide uptake in choroid plexus.

The presence of multiple oligopeptide transporters in brain has generated considerable interest as to their physiological role in neuropeptide homeostasis, pharmacologic importance, and potential as a target for drug delivery through the blood-brain and blood-cerebrospinal fluid barriers. To understand further the purpose of specific peptide transporters in brain, we have generated PEPT2-deficient mice by targeted gene disruption. Homozygous PepT2 null mice lacked expression of PEPT2 mRNA and protein in choroid plexus and kidney, tissues in which PepT2 is normally expressed, whereas heterozygous mice displayed PepT2 expression levels that were intermediate between those of wild-type and homozygous null animals. Mutant PepT2 null mice were found to be viable, grew to normal size and weight, and were without obvious kidney or brain abnormalities. Notwithstanding the lack of apparent biological effects, the proton-stimulated uptake of 1.9 microm glycylsarcosine (a model, hydrolysis-resistant dipeptide) in isolated choroid plexus was essentially ablated (i.e. residual activity of 10.9 and 3.9% at 5 and 30 min, respectively). These novel findings provide strong evidence that, under the experimental conditions of this study, PEPT2 is the primary member of the peptide transporter family responsible for dipeptide uptake in choroid plexus tissue.