1.The IGF-derived tripeptide Gly-Pro-Glu is a weak NMDA receptor agonist.
Vaaga CE1, Tovar KR2, Westbrook GL2. J Neurophysiol. 2014 Sep 15;112(6):1241-5. doi: 10.1152/jn.00290.2014. Epub 2014 Jun 18.
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 Mg(2+).
2.Molecular mechanism underlying the cerebral effect of Gly-Pro-Glu tripeptide bound to L-dopa in a Parkinson's animal model.
Minelli A1, Conte C, Cacciatore I, Cornacchia C, Pinnen F. Amino Acids. 2012 Sep;43(3):1359-67. doi: 10.1007/s00726-011-1210-x. Epub 2012 Jan 5.
Oxidative stress is a critical contributing factor to neurodegenerative disorders. Therefore, the inhibition of ROS formation, responsible for chronic detrimental neuroinflammation, is an important strategy for preventing the neurodegenerative disease and for neuroprotective therapy. Gly-Pro-Glu (GPE) is the N-terminal tripeptide of insulin-like growth factor-I, which is naturally cleaved in the plasma and brain tissues. GPE has neuroprotective effects since it crosses the blood-CSF and the functional CSF-brain barriers and binds to glial cells. It has been shown that GPE improves motor behaviour in rats after 6-OHDA lesion, although it does not rescue dopaminergic neurons. Thus, we hypothesized that the GPE therapeutic efficacy in a Parkinson model might be improved by combining GPE to L: -dopa. Here, we used an animal model that represents a progressive chronic Parkinson's disease (PD) model, characterized by high levels of oxidative stress and inflammation.
