Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 35, Issue 10, Pages 1712-1726Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01332-14
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Funding
- National Science Council [NSC 99-2321-B-010-015, 96-2320-B-010-039-MY3, 100-2320-B-010-033-MY2, MOST 103-2325-B-039-006]
- Aim for the Top University Plan from the Ministry of Education
- Department of Health Clinical Trial and Research Center of Excellence, Taiwan [DOH 101-TD-B-111-004, 104-TDU-B-212-113002, BM104010092]
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Growth-associated protein 43 (GAP43) is known to regulate axon growth, but whether it also plays a role in synaptogenesis remains unclear. Here, we found that GAP43 regulates the aggregation of gephyrin, a pivotal protein for clustering postsynaptic GABA(A) receptors (GABA(A)Rs), in developing cortical neurons. Pharmacological blockade of either protein kinase C (PKC) or neuronal activity increased both GAP43-gephyrin association and gephyrin misfolding-induced aggregation, suggesting the importance of PKC-dependent regulation of GABAergic synapses. Furthermore, we found that PKC phosphorylation-resistant GAP43(S41A), but not PKC phosphorylation-mimicking GAP43(S41D), interacted with cytosolic gephyrin to trigger gephyrin misfolding and its sequestration into aggresomes. In contrast, GAP43(S41D), but not GAP43(S41A), inhibited the physiological aggregation/clustering of gephyrin, reduced surface GABA(A)Rs under physiological conditions, and attenuated gephyrin misfolding under transient oxygen-glucose deprivation (tOGD) that mimics pathological neonatal hypoxia. Calcineurin-mediated GAP43 dephosphorylation that accompanied tOGD also led to GAP43-gephyrin association and gephyrin misfolding. Thus, PKC-dependent phosphorylation of GAP43 plays a critical role in regulating postsynaptic gephyrin aggregation in developing GABAergic synapses.
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