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The novel caspase-3 substrate Gap43 is involved in AMPA receptor endocytosis and long-term depression.

The cysteine protease caspase-3, best known as an executioner of cell death in apoptosis, also plays a non-apoptotic role in N-methyl-d-aspartate receptor-dependent long-term depression of synaptic transmission (NMDAR-LTD) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor endocytosis in neurons. The mechanism by which caspase-3 regulates LTD and AMPA receptor endocytosis, however, remains unclear. Here, we addressed this question by using an enzymatic N-terminal peptide enrichment method and mass spectrometry to identify caspase-3 substrates in neurons. Of the many candidates revealed by this proteomic study, we have confirmed BASP1, Dbn1, and Gap43 as true caspase-3 substrates. Moreover, in hippocampal neurons, Gap43 mutants deficient in caspase-3 cleavage inhibit AMPA receptor endocytosis and LTD. We further demonstrated that Gap43, a protein well-known for its functions in axons, is also localized at postsynaptic sites. Our study has identified Gap43 as a key caspase-3 substrate involved in LTD and AMPA receptor endocytosis, uncovered a novel postsynaptic function for Gap43 and provided new insights into how long-term synaptic depression is induced.

Pubmed ID: 24023391 RIS Download

Mesh terms: Animals | Caspase 3 | Embryo, Mammalian | Endocytosis | GAP-43 Protein | Gene Expression Regulation, Developmental | Hippocampus | Long-Term Synaptic Depression | Neuronal Plasticity | Neurons | Patch-Clamp Techniques | Primary Cell Culture | Protein Binding | Protein Interaction Mapping | Rats | Rats, Sprague-Dawley | Receptors, AMPA | Receptors, N-Methyl-D-Aspartate | Synapses | Synaptic Transmission | Tissue Culture Techniques

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Associated grants

  • Agency: NIMH NIH HHS, Id: ZIA MH000279
  • Agency: PHS HHS, Id: 1ZIAMH00279-27
  • Agency: PHS HHS, Id: 1ZIAMH000274-35
  • Agency: NIMH NIH HHS, Id: ZIA MH000274
  • Agency: NIMH NIH HHS, Id: ZIA MH002881
  • Agency: PHS HHS, Id: 1ZIAMH002881

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