1. The novel caspase-3 substrate Gap43 is involved in AMPA receptor endocytosis and long-term depression.
- Author
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Han MH, Jiao S, Jia JM, Chen Y, Chen CY, Gucek M, Markey SP, and Li Z
- Subjects
- Animals, Caspase 3 metabolism, Embryo, Mammalian, Endocytosis, GAP-43 Protein metabolism, Gene Expression Regulation, Developmental, Hippocampus cytology, Hippocampus growth & development, Neuronal Plasticity genetics, Neurons cytology, Patch-Clamp Techniques, Primary Cell Culture, Protein Binding, Protein Interaction Mapping, Rats, Rats, Sprague-Dawley, Receptors, AMPA metabolism, Receptors, N-Methyl-D-Aspartate genetics, Receptors, N-Methyl-D-Aspartate metabolism, Synapses genetics, Synapses metabolism, Tissue Culture Techniques, Caspase 3 genetics, GAP-43 Protein genetics, Hippocampus metabolism, Long-Term Synaptic Depression genetics, Neurons metabolism, Receptors, AMPA genetics, Synaptic Transmission genetics
- Abstract
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.
- Published
- 2013
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