Stimulation of Na+/Cl-coupled opioid peptide transport system in SK-N-SH cells by L-kyotorphin, an endogenous substrate for H+-coupled peptide transporter PEPT2

Santoshanand V. Thakkar, Seiji Miyauchi, Puttur D. Prasad, Vadivel Ganapathy

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


We have recently identified a Na+/Cl - coupled transport system in mammalian cells for endogenous and synthetic opioid peptides. This transport system does not transport dipeptides/ tripeptides, but is stimulated by these small peptides. Here we investigated the influence of L-kyotorphin (L-Tyr-L-Arg), an endogenous dipeptide with opioid activity, on this transport system. The activity of the transport system, measured in SK-N-SH cells (a human neuronal cell line) with deltorphin II as a model substrate, was stimulated ∼2.5-fold by L-kyotorphin, with half-maximal stimulation occurring at∼100 μM. The stimulation was associated primarily with an increase in the affinity for deltorphin II. The stimulation caused by L-kyotorphin was stereospecific; L-Tyr-D-Arg (D-kyotorphin) had minimal effect. The influence of L-kyotorphin was observed also in a different cell line which expressed the opioid peptide transport system. While L-kyotorphin is a stimulator of opioid peptide transport, it is a transportable substrate for the H+-coupled peptide transporter PEPT2, which is expressed widely in the brain. Since the activity of the opioid peptide transport system is modulated by extracellular L-kyotorphin and since PEPT2 is an important determinant of extracellular Lkyotorphin in the brain, the expression/activity of PEPT2 may be a critical factor in the modulation of opioidergic neurotransmission in vivo.

Original languageEnglish (US)
Pages (from-to)254-262
Number of pages9
JournalDrug Metabolism and Pharmacokinetics
Issue number4
StatePublished - 2008


  • Kyotorphin
  • Opioid peptide transport
  • Opioidergic neurotransmission
  • PEPT2
  • SK-N-SH cell line
  • Stereospecificity

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)


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