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

Zhu, Ling‐Qiang; Liú, Dan; Hu, Juan; Cheng, Jin Q.; Wang, Shaohui; Wang, Qun; Wang, Fang; Chen, Jianguo; Wang, Jian‐Zhi

doi:10.1523/jneurosci.5223-09.2010

Cited by 90 publications

(83 citation statements)

References 55 publications

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“…To clarify the related signaling components downstream of the MT2 receptor, we first examined the glycogen synthase kinase-3β (GSK-3β) and collapsin response mediator protein-2 (CRMP-2), which are widely recognized mediators for specifying axon/dendrite fate and synaptic activity. [29][30][31] In rat hippocampal neuron cultures, we found that activation of the MT2 receptor by MEL or IIK7 led to inactivation of GSK-3β and this inactivation was associated with an increased level of dephosphorylated CRMP-2 at Thr514 Since Akt is the most recognized upstream regulator of GSK-3β, 32 we studied whether Akt links the MT2 receptor to GSK-3β and the CRMP-2 pathway. We found that phosphorylation of Akt at serine473 (pS473-Akt, an activated form of Akt) increased when MT2 was activated by MEL or IIK7, whereas the level of These results suggest that MT2 receptor activation promotes functional synaptogenesis through the Akt/GSK-3β/CRMP-2 pathway.…”

Section: Resultsmentioning

confidence: 99%

“…Cultures of dissociated hippocampal neurons were prepared from embryonic E18 rats as previously described. 29,44 The hippocampi of embryos were dissected and trypsinized by TrypLE Express (Invitrogen, Grand Island, NY, USA) for 15 min at 37°C. Dissociated neurons were plated onto poly-D-lysine (Sigma) coated Figure 6 MT2 receptor is linked with Akt/GSK-3β/CRMP2 pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Cultured neurons or brain sections were immunostained by previously described methods. 29,44 Neurons and brain sections were incubated in primary antibodies for 12-36 h at 4°C and subsequently with AlexaFluro 488-and AlexaFluro 546-conjugated secondary antibodies. Images were examined by using a Zeiss LSM510 laser confocal microscope (Zeiss, Jena, Germany) or an Olympus IX70 fluorescence microscope (Olympus, Tokyo, Japan).…”

Section: Discussionmentioning

confidence: 99%

“…The western blotting was carried out by a well-established procedure in our laboratory. 29,44 Briefly, the cell extracts prepared from HEK 293 or cultured neurons were separated by SDS-PAGE (10%) and the proteins were transferred onto nitrocellulose membrane (Amersham, Piscataway, NJ, USA) for 1 h using the transfer apparatus (Bio-Rad, Berkeley, CA, USA). After block with 3% milk for 30 min at room temperature, the membranes were then incubated at 4°C with primary antibodies overnight.…”

Section: Discussionmentioning

confidence: 99%

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The MT2 receptor stimulates axonogenesis and enhances synaptic transmission by activating Akt signaling

Man

et al. 2014

Cell Death Differ

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The MT2 receptor is a principal type of G protein-coupled receptor that mainly mediates the effects of melatonin. Deficits of melatonin/MT2 signaling have been found in many neurological disorders, including Alzheimer's disease, the most common cause of dementia in the elderly, suggesting that preservation of the MT2 receptor may be beneficial to these neurological disorders. However, direct evidence linking the MT2 receptor to cognition-related synaptic plasticity remains to be established. Here, we report that the MT2 receptor, but not the MT1 receptor, is essential for axonogenesis both in vitro and in vivo. We find that axon formation is retarded in MT2 receptor knockout mice, MT2-shRNA electroporated brain slices or primary neurons treated with an MT2 receptor selective antagonist. Activation of the MT2 receptor promotes axonogenesis that is associated with an enhancement in excitatory synaptic transmission in central neurons. The signaling components downstream of the MT2 receptor consist of the Akt/GSK-3β/CRMP-2 cascade. The MT2 receptor C-terminal motif binds to Akt directly. Either inhibition of the MT2 receptor or disruption of MT2 receptor-Akt binding reduces axonogenesis and synaptic transmission. Our data suggest that the MT2 receptor activates Akt/GSK-3β/CRMP-2 signaling and is necessary and sufficient to mediate functional axonogenesis and synaptic formation in central neurons. Synaptic circuits are established at the sites of axon-dendritic, axon-somatic or axon-axonal contact, in which functional axonogenesis is a critical step. 1 Axonogenesis can be regulated by many intracellular signals that involve cytoskeletal rearrangements, 2 local protein degradation, 3 as well as diffusional barriers. 4 Additionally, several extracellular neurotrophic factors and hormones have also been shown to have a role in axon guidance and synaptic formation in central neurons. 5,6 To date, the role of melatonin and its receptors in axonogenesis remains unclear. Most of the biological functions of melatonin are mediated by its two receptors, MT1 and MT2 receptors, both of them belong to the G protein-coupled receptor (GPCR) subfamily and are widely expressed throughout the central nervous system (CNS). 7 Activation of the MT2 receptor in response to melatonin is critical for controlling circadian rhythms 7 and regulation of slow wave sleep. 8,9 Early studies have shown that activation of the MT2 receptor in the retina reduces the release of dopamine, while dopamine inhibits growth cone motility and neurite outgrowth during embryonic development, 10,11 suggesting the involvement of the MT2 receptor in functional axonogenesis. In mutant mice with deficient expression of the MT2 gene, the induction of long-term potentiation (LTP) of excitatory synaptic transmission is impaired, and this impairment is closely related to deficits in learning. 12 In the hippocampus, the MT2 receptor inhibits GABA A receptor-mediated current, 13 which is implicated in the synaptic transmission. In Alzheimer's disease, expression of the MT...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The MT2 receptor stimulates axonogenesis and enhances synaptic transmission by activating Akt signaling

Man

et al. 2014

Cell Death Differ

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“…Detailed electrophysiological recordings were as described previously [30] . Briefl y, initial baseline responses were obtained by delivering a single pulse of stimulation once every 30 s.…”

Section: Electrophysiological Recordingmentioning

confidence: 99%

Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid β-peptide in rats

Chai

Duan

et al. 2014

Neurosci. Bull.

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Amyloid β-peptide (Aβ) has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer's disease (AD). Humanin (HN) is a secretory peptide that inhibits the neurotoxicity of Aβ. However, the mechanism(s) by which HN exerts its neuroprotection against Aβ-induced ADlike pathological changes and memory deficits are yet to be completely defined. In the present study, we provided evidence that treatment of rats with HN increases the number of dendritic branches and the density of dendritic spines, and upregulates pre-and post-synaptic protein levels; these effects lead to enhanced long-term potentiation and amelioration of the memory deficits induced by Aβ 1-42 . HN also attenuated Aβ 1-42 -induced tau hyperphosphorylation, apparently by inhibiting the phosphorylation of Tyr307 on the inhibitory protein phosphatase-2A (PP2A) catalytic subunit and thereby activating PP2A. HN also inhibited apoptosis and reduced the oxidative stress induced by Aβ 1-42 . These fi ndings provide novel mechanisms of action for the ability of HN to protect against Aβ 1-42 -induced AD-like pathological changes and memory defi cits.

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Exocytotic Machinery as a Target for the Development of New Drugs for Schizophrenia

Guerrero¹,

Hormaeche²,

Uribarri³

et al. 2012

Therapeutic Targets

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

Cited by 90 publications

References 55 publications

The MT2 receptor stimulates axonogenesis and enhances synaptic transmission by activating Akt signaling

The MT2 receptor stimulates axonogenesis and enhances synaptic transmission by activating Akt signaling

Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid β-peptide in rats

Exocytotic Machinery as a Target for the Development of New Drugs for Schizophrenia

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