GSK-3β Inhibits Presynaptic Vesicle Exocytosis by Phosphorylating P/Q-Type Calcium Channel and Interrupting SNARE Complex Formation

作者：Zhu, Ling-Qiang^*; Liu, Dan; Hu, Juan; Cheng, Jin; Wang, Shao-Hui; Wang, Qun; Wang, Fang; Chen, Jian-Guo; Wang, Jian-Zhi

来源：Journal of Neuroscience, 2010, 30(10): 3624-3633.

DOI：10.1523/JNEUROSCI.5223-09.2010

• GLYCOGEN-SYNTHASE KINASE-3
• LONG-TERM POTENTIATION
• N-TYPE
• NEUROTRANSMITTER RELEASE
• SUBCELLULAR-DISTRIBUTION
• CULTURING HIPPOCAMPAL
• SYNAPTIC-TRANSMISSION
• SYMPATHETIC NEURONS
• PROTEIN-KINASE
• CA2+ CHANNELS

Glycogen synthase kinase-3 (GSK-3), a Ser/Thr protein kinase abundantly expressed in neurons, plays diverse functions in physiological and neurodegenerative conditions. Our recent study shows that upregulation of GSK-3 suppresses long-term potentiation and presynaptic release of glutamate; however, the underlying mechanism is elusive. Here, we show that activation of GSK-3 beta retards the synaptic vesicle exocytosis in response to membrane depolarization. Using calcium imaging, whole-cell patch-clamp, as well as specific Ca2+ channel inhibitors, we demonstrate that GSK-3 beta phosphorylates the intracellular loop-connecting domains II and III (LII-III) of P/Q-type Ca2+ channels, which leads to a decrease of intracellular Ca2+ rise through the P/Q-type voltage-dependent calcium channel. To further illustrate the mechanisms of GSK-3 beta's action, we show that activation of GSK-3 beta interferes with the formation of the soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) complex through: (1) weakening the association of synaptobrevin with SNAP25 and syntaxin; (2) reducing the interactions among the phosphorylated LII-III and synaptotagmin, SNAP25, and syntaxin; and (3) inhibiting dissociation of synaptobrevin from synaptophysin I. These results indicate that GSK-3 beta negatively regulates synaptic vesicle fusion events via interfering with Ca2+-dependent SNARE complex formation.

• 出版日期2010-3-10
• 单位华中科技大学