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.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
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