ENDOGENOUS PEPTIDE TYR-PRO-TRP-GLY-NH2 (TYR-W-MIF-1) IS TRANSPORTED FROM THE BRAIN TO THE BLOOD BY PEPTIDE-TRANSPORT SYSTEM-1

Tyr-W-MIF-1 (Tyr-Pro-TrP-Gly-NH2) is a recently isolated peptide that belongs to a larger family that includes Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) and MIF-1 (Pro-Leu-Gly-NH2). Despite similarities in structure, Tyr-MIF-1 and MIF-1 can act differently in behavioral, blood-brain barrier (BBB) transport, and receptor binding systems. Tyr-W-MIF-1, like Tyr-MIF-1, has both opiate and antiopiate activity, but may be more opiate-like than Tyr-MIF-1. Tyr-MIF-1, but not MIF-1, is transported from brain to blood by peptide transport system (PTS)-1. PTS-1 transports mainly Tyr-MIF-1 and methionine enkephalin, but does not transport amino acids, peptide fragments of Tyr-MIF-1, D-Tyr-MIF-1, or unrelated peptides and proteins. We tested whether Tyr-W-MIF-1 also was transported across the BBB and, if so, whether PTS-1 was involved. I-125-Tyr-W-MIF-1 had a half-time disappearance from the brain of 22.4 min. This is faster than the efflux occurring with nonsaturable reabsorption of the cerebrospinal fluid and, therefore, is consistent with saturable transport, but it is slower than the efflux rate of Tyr-MIF-1, suggesting a less robust transport than for Tyr-MIF-1. Self-inhibition with excess unlabeled Tyr-W-MIF-1 confirmed a saturable component, with a dose of 4.2 nmol producing 50% inhibition. Competition studies between radioactively labeled Tyr-W-MIF-1 and unlabeled Tyr-MIF-1 and between labeled Tyr-MIF-1 and unlabeled Tyr-W-MIF-1 showed that Tyr-W-MIF-1 is transported by PTS-1 with Tyr-MIF-1 being the preferred ligand. Aluminum and serotonergic agents modulate PTS-1 activity and they affected Tyr-W-MIF-1 transport in a manner consistent with its mediation through PTS-1. It is concluded that Tyr-W-MIF-1 is transported out of the brain by a saturable system that is probably PTS-1, although transport is less robust than that of Tyr-MIF-1. (C) Wiley-Liss, Inc.