QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.116806v1 321/1/257    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Miyauchi, S. Articles by Ganapathy, V. Search for Related Content PubMed PubMed Citation Articles by Miyauchi, S. Articles by Ganapathy, V.

METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Differential Modulation of Sodium- and Chloride-Dependent Opioid Peptide Transport System by Small Nonopioid Peptides and Free Amino Acids

Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia (S.M., E.G., S.V.T., P.D.P., V.G.); and Laboratory of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan (S.I.)

We recently identified a novel opioid peptide transport system in the retinal pigment epithelium that transports opioid peptides by a Na⁺/Cl^–-dependent process. Here we describe a similar transport system expressed in SK-N-SH cells (a human neuronal cell line) and show for the first time that the activity of the transport system is modulated differentially by lysine and small nonopioid peptides. The transport process in SK-N-SH cells, monitored with deltorphin II as the substrate, is Na⁺/Cl^–-dependent and interacts with several opioid peptides, consisting of 5 to 13 amino acids. The activity of this transport system is markedly stimulated by specific dipeptides and tripeptides, with significant stimulation observable at low micromolar concentrations. The ion dependence, Na⁺/Cl^–-activation kinetics, and opioid peptide selectivity of the transport system, however, remain unchanged. The stimulation by the modulatory peptides is associated with an increase in maximal velocity with no change in substrate affinity of the system. Amino acids have no or little effect on the transport system, with the exception of lysine. This cationic amino acid inhibits the transport system, with significant inhibition occurring at physiologic concentrations of the amino acid. The inhibitory effect is primarily associated with a decrease in the maximal velocity of the transport system with little change in substrate affinity. Methyl and ethyl esters of lysine retain the inhibitory potency, but most other structural analogs have no effect. The differential modulation of the transport system by lysine and specific small peptides has important implications in the biology and pharmacology of opioid peptides.

Address correspondence to: Dr. Vadivel Ganapathy, Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912. E-mail: vganapat{at}mail.mcg.edu