The present address of Hong Shen is the Dev MAP, Bristol-Myers Squibb, F1.2103B, Route 206 & Province Line Road, Princeton, NJ 08543, USA.
Peptide transporter 2 (PEPT2) expression in brain protects against 5-aminolevulinic acid neurotoxicity
Article first published online: 9 AUG 2007
Journal of Neurochemistry
Volume 103, Issue 5, pages 2058–2065, December 2007
How to Cite
Hu, Y., Shen, H., Keep, R. F. and Smith, D. E. (2007), Peptide transporter 2 (PEPT2) expression in brain protects against 5-aminolevulinic acid neurotoxicity. Journal of Neurochemistry, 103: 2058–2065. doi: 10.1111/j.1471-4159.2007.04905.x
- Issue published online: 9 AUG 2007
- Article first published online: 9 AUG 2007
- Received June 14, 2007; revised manuscript received July 31, 2007; accepted July 31, 2007.
- 5-aminolevulinic acid;
- peptide transporter 2
The proton-coupled oligopeptide transporter PEPT2 (or SLC15A2) is the major protein involved in the reclamation of peptide-bound amino acids and peptide-like drugs in kidney. PEPT2 is also important in effluxing peptides and peptidomimetics from CSF at the choroid plexus, thereby limiting their exposure in brain. In this study, we report a neuroprotective role for PEPT2 in modulating the toxicity of a heme precursor, 5-aminolevulinic acid (5-ALA). Our findings demonstrate that in PEPT2-deficient mice, 5-ALA administration results in reduced survivability, a worsening of neuromuscular dysfunction, and CSF concentrations of substrate that are 8–30 times higher than that in wild-type control animals. The ability of PEPT2 to limit 5-ALA exposure in CSF suggests that it may also have relevance as a secondary genetic modifier of conditions (such as acute hepatic porphyrias and lead poisoning) in which 5-ALA metabolism is altered and in which 5-ALA toxicity is important.