New Modes of GPCR Signalling

ABSTRACT
The Synaptic Mechanisms of Glycogen Synathese Kinase-3 in Regulating
Leaning and Memory
Jian-Zhi Wang, Ling-Qiang Zhu, Dan Liu, Juan Hu, Qun Wang
Pathophysiology Department, Key Laboratory of Education Committee on
Neurological Disorders, Tongji Medical College, Huazhong University of Science and
Technology, Wuhan, China
Previous studies have demonstrated that upregulation of glycogen synathese kinase-3
(GSK-3 ) impairs learning
and memory in rats and transgenic mouse models, and
ctivation of GSK-3 inhibits long term potentiation with mechanisms involving a
decreased presynaptic glutamate release. To further verify the mechanisms underlying
the impaired synaptic vesicle exocytosis, we have recently demonstrated that activation
of GSK-3 could inhibit calcium influx through phosphorylating the intracellular loop
connecting domains II and III (LII-III) of P/Q-type Ca 2+ channels, which leads to
decrease of intracellular Ca 2+ influx through the P/Q-type voltage-dependent calcium
channel (VDCC). GSK-3 interferes with the formation of SNARE complex through (i)
weakening the association of synaptobrevin with SNAP25 and syntaxin; (ii) reducing
the interaction between the phosphorylated LII-III and synaptotagmin, SNAP25 and
syntaxin; and (iii) inhibiting dissociation of synaptobrevin from synaptophysin I, all of
which are required for SNARE complex formation and thus for an efficient exocytosis.
These results suggest that GSK-3 regulates
synaptic vesicle cycle by affecting
multiple steps in vesicular exocytosis.