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Mol Cell Biol：Protein kinase C-dependent growth-associated

2015-06-07 15:46 来源：编辑：麻晓点击:

2015 May 15;35(10):1712-26. doi: 10.1128/MCB.01332-14. Epub 2015 Mar 9.

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

Wang CY¹, Lin HC², Song YP³, Hsu YT³, Lin SY⁴, Hsu PC², Lin CH⁵, Hung CC⁶, Hsu MC³, Kuo YM⁷, Lee YJ⁸, Hsu CY⁹, Lee YH¹⁰.

Author information

¹Department and Institute of Physiology and Brain Research Center, National Yang-Ming University, Taipei, Taiwan Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan Graduate Institute of Clinical Medical Science and Department of Neurology, China Medical University and Hospital, Taichung, Taiwan.
²Department and Institute of Physiology and Brain Research Center, National Yang-Ming University, Taipei, Taiwan.
³Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
⁴Common Mass Spectrometry Facilities at Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
⁵Nursing, Kang-Ning Junior College of Medical Care and Management, Taipei, Taiwan.
⁶Department and Institute of Physiology and Brain Research Center, National Yang-Ming University, Taipei, Taiwan Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
⁷Department and Institute of Physiology and Brain Research Center, National Yang-Ming University, Taipei, Taiwan Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan.
⁸School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan.
⁹Graduate Institute of Clinical Medical Science and Department of Neurology, China Medical University and Hospital, Taichung, Taiwan.
¹⁰Department and Institute of Physiology and Brain Research Center, National Yang-Ming University, Taipei, Taiwan Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan yhlee3@ym.edu.tw.

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 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 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.

PMID:: 25755278; [PubMed - in process]
PMCID:: PMC4405633; [Available on 2015-11-01]

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