The IGF-derived tripeptide Gly-Pro-Glu is a weak NMDA receptor agonist

Christopher E. Vaaga, Kenneth R. Tovar, Gary L. Westbrook

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Glutamate acts as the universal agonist at ionotropic glutamate receptors in part because of its high degree of conformational flexibility. Other amino acids and small peptides, however, can activate N-methyl-D-aspartate (NMDA) receptors, albeit usually with lower affinity and efficacy. Here, we examined the action of glycine-proline-glutamate (GPE), a naturally occurring tripeptide formed in the brain following cleavage of IGF-I. GPE is thought to have biological activity in the brain, but its mechanism of action remains unclear. With its flanking glutamate and glycine residues, GPE could bind to either the agonist or coagonist sites on NMDA receptors, however, this has not been directly tested. Using whole cell patch-clamp recordings in combination with rapid solution exchange, we examined both steady-state currents induced by GPE as well as the effects of GPE on synaptically evoked currents. High concentrations of GPE evoked inward currents, which were blocked either by NMDA receptor competitive antagonists or the voltage-dependent channel blocker Mg2+. GPE also produced a slight attenuation in the NMDA- and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-mediated excitatory postsynaptic currents without altering the paired-pulse ratio. Our results suggest that GPE can activate NMDA receptors but at concentrations well above the expected concentration of GPE in the brain. Therefore, it is unlikely that endogenous GPE interacts with glutamate receptors under normal conditions.

Original languageEnglish (US)
Pages (from-to)1241-1245
Number of pages5
JournalJournal of neurophysiology
Issue number6
StatePublished - Sep 15 2014


  • GPE
  • Glutamate receptors
  • Hippocampal neuron
  • IGF
  • Peptide

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology


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