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

Chen Yu Wang, Hui Ching Lin, Yi Ping Song, Yu Ting Hsu, Shu Yu Lin, Pei Chien Hsu, Chun Hua Lin, Chia Chi Hung, Min Ching Hsu, Yi Min Kuo, Yih Jing Lee, Chung Y. Hsu, Yi Hsuan Leea

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11 Citations (Scopus)

Abstract

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 GABAA receptors (GABAARs), 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 GAP43S41A, but not PKC phosphorylation-mimicking GAP43S41D, interacted with cytosolic gephyrin to trigger gephyrin misfolding and its sequestration into aggresomes. In contrast, GAP43S41D, but not GAP43S41A, inhibited the physiological aggregation/clustering of gephyrin, reduced surface GABAARs 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.

Original languageEnglish
Pages (from-to)1712-1726
Number of pages15
JournalMolecular and Cellular Biology
Volume35
Issue number10
DOIs
Publication statusPublished - 2015
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Medicine(all)

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    Wang, C. Y., Lin, H. C., Song, Y. P., Hsu, Y. T., Lin, S. Y., Hsu, P. C., Lin, C. H., Hung, C. C., Hsu, M. C., Kuo, Y. M., Lee, Y. J., Hsu, C. Y., & Leea, Y. H. (2015). Protein kinase C-dependent growth-associated protein 43 phosphorylation regulates gephyrin aggregation at Developing GABAergic synapses. Molecular and Cellular Biology, 35(10), 1712-1726. https://doi.org/10.1128/MCB.01332-14