title: The novel caspase-3 substrate Gap43 is involved in AMPA receptor endocytosis and long-term depression.
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.
authors.affiliation: National Institute of Mental Health, Bethesda, Maryland 20892;
authors.forename: Meng-Hsuan
authors.initials: MH
authors.lastname: Han
authors.forename: Song
authors.initials: S
authors.lastname: Jiao
authors.forename: Jie-Min
authors.initials: JM
authors.lastname: Jia
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Cai Yun
authors.initials: CY
authors.lastname: Chen
authors.forename: Marjan
authors.initials: M
authors.lastname: Gucek
authors.forename: Sanford P
authors.initials: SP
authors.lastname: Markey
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian; D004705:Endocytosis; D019922:GAP-43 Protein / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D036881:Long-Term Synaptic Depression / Q000235:genetics*; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D061251:Primary Cell Culture; D011485:Protein Binding; D025941:Protein Interaction Mapping; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics*; D046509:Tissue Culture Techniques
chemical_list: D019922:GAP-43 Protein; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D053148:Caspase 3
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