RGD Reference Report - Protein kinase C-dependent growth-associated protein 43 phosphorylation regulates gephyrin aggregation at developing GABAergic synapses. - Rat Genome Database

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Protein kinase C-dependent growth-associated protein 43 phosphorylation regulates gephyrin aggregation at developing GABAergic synapses.

Authors: Wang, Chen-Yu  Lin, Hui-Ching  Song, Yi-Ping  Hsu, Yu-Ting  Lin, Shu-Yu  Hsu, Pei-Chien  Lin, Chun-Hua  Hung, Chia-Chi  Hsu, Min-Ching  Kuo, Yi-Min  Lee, Yih-Jing  Hsu, Chung Y  Lee, Yi-Hsuan 
Citation: Wang CY, etal., Mol Cell Biol. 2015 May;35(10):1712-26. doi: 10.1128/MCB.01332-14. Epub 2015 Mar 9.
RGD ID: 13702431
Pubmed: (View Article at PubMed) PMID:25755278
DOI: Full-text: DOI:10.1128/MCB.01332-14

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.

Annotation

Gene Ontology Annotations    

Biological Process

Cellular Component
GABA-ergic synapse  (IDA,IMP)

Objects Annotated

Genes (Rattus norvegicus)
Gap43  (growth associated protein 43)


Additional Information