Neuroprotection by cell permeable TAT-mGluR1 peptide in ischemia: synergy between carrier and cargo sequences.
Overactivation of glutamate receptors is a critical mechanism for neuronal death in ischemic stroke. Previously, we reported that overactivation of N-methyl-D-aspartate (NMDA)-type glutamate receptor induced calpain-mediated truncation of metabotropic glutamate receptor mGluR1alpha, resulting in suppression of its neuroprotective signaling pathway. A fusion peptide containing the transactivating regulatory protein (TAT) protein transduction domain (PTD) and the mGluR1alpha sequence spanning the calpain cleavage site effectively blocked mGluR1alpha truncation and protected neurons against NMDA-induced neuronal toxicity. We recently evaluated the role of this mechanism in ischemia-induced cell death. We found that mGluR1alpha was truncated in both in vitro and in vivo models of stroke and that this truncation was accompanied by the typical calpain-mediated proteolysis of spectrin. The TAT-mGluR1 fusion peptide produced robust neuroprotective effect in the in vitro model of stroke. In addition, we found that the TAT protein transduction domain peptide itself altered the function of membrane channels through some unknown mechanisms and showed some mild neuroprotective effects. Together, these experiments indicated a synergistic relationship between the TAT carrier sequence and the mGluR1alpha peptide cargo sequence, and this synergy might account for the neuroprotective properties of the TAT-mGluR1 peptide.
Wei Xu
Neuroscience Program University of Southern California, Los Angeles, California 90089-2520, USA.
Miou Zhou
Baudry
Michel
M
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D015696:Gene Products, tat / Q000737:chemistry; D006801:Humans; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
D015696:Gene Products, tat; D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; C534738:TAT-mGluR1 peptide; C104077:metabotropic glutamate receptor type 1