Cophosphorylation of amphiphysin I and dynamin I by Cdk5 regulates clathrin-mediated endocytosis of synaptic vesicles

Tomizawa, Kazuhito; Sunada, Satoshi; Lu, Yun; Oda, Yoshiya; Kinuta, Masahiro; Ohshima, Toshio; Saito, Taro; Wei, Fan Yan; Matsushita, Masayuki; Li, Shengtian; Tsutsui, Kimiko; Hisanaga, Shin Ichi; Mikoshiba, Katsuhiko; Takei, Kohji; Matsui, Hideki

doi:10.1083/jcb.200308110

Cited by 180 publications

(246 citation statements)

References 36 publications

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“…As a result of this work, it has been shown that dynamin 1 was significantly reduced not only in the hippocampus of an AD mouse model and in cultured hippocampal neurons treated with Aβ but also in the brain of AD patients (Yao et al 2003;Kelly et al 2005;Kelly and Ferreira 2006). The mechanisms leading to this dynamin 1 depletion seem to involve calpain, a protease system that is active in AD (Tsuji et al 1998;Lee et al 2000;Battaglia et al 2003;Tomizawa et al 2003;Chen and Fernandez 2005;Demuro et al 2005;Gong et al 2005;Kelly et al 2005;Fifre et al 2006;Kelly and Ferreira 2006). Furthermore, we have reported that this Aβ-mediated dynamin 1 degradation was the result of calpain activation induced by the sustained calcium influx mediated by N-methyl-D-aspartate (NMDA) receptors in hippocampal neurons (Kelly and Ferreira 2006).…”

Section: Discussionmentioning

confidence: 99%

Beta-amyloid disrupted synaptic vesicle endocytosis in cultured hippocampal neurons

Kelly¹,

Ferreira²

2007

Neuroscience

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Neuronal death leading to gross brain atrophy is commonly seen in Alzheimer's disease (AD) patients. Yet, it is becoming increasingly apparent that the pathogenesis of AD involves early and more discrete synaptic changes in affected brain areas. However, the molecular mechanisms that underlie such synaptic dysfunction remain largely unknown. Recently, we have identified dynamin 1, a protein that plays a critical role in synaptic vesicle endocytosis, and hence, in the signaling properties of the synapse, as a potential molecular determinant of such dysfunction in AD. In the present study, we analyzed beta-amyloid (Aβ)-induced changes in synaptic vesicle recycling in cultured hippocampal neurons. Our results showed that Aβ, the main component of senile plaques, caused ultrastructural changes indicative of impaired synaptic vesicle endocytosis in cultured hippocampal neurons that have been stimulated by depolarization with high potassium. In addition, Aβ led to the accumulation of amphiphysin in membrane fractions from stimulated hippocampal neurons. Moreover, experiments using FM1-43 showed reduced dye uptake in stimulated hippocampal neurons treated with Aβ when compared to untreated stimulated controls. Similar results were obtained using a dynamin 1 inhibitory peptide suggesting that dynamin 1 depletion caused deficiency in synaptic vesicle recycling not only in Drosophila but also in mammalian neurons. Collectively, these results showed that Aβ caused a disruption of synaptic vesicle endocytosis in cultured hippocampal neurons. Furthermore, we provided evidence suggesting that Aβ-induced dynamin 1 depletion might play an important role in this process. Keywords synaptic dysfunction; amphiphysin; beta-amyloid; endocytosis; FM1-43 Alzheimer disease (AD) is a debilitating disorder that leads to significant cognitive deficits. Pathologically, AD is characterized by the presence of extracellular senile plaques, composed of the amyloid-beta protein (Aβ), and intraneuronal neurofibrillary tangles, composed of the tau protein (Glenner and Wong 1984;Grundke-Iqbal et al. 1986). In addition, significant atrophy due to the loss of neurons in the cholinergic and glutamatergic areas of the brain have been detected in this disease (Teipel et al. 2005;van de Pol et al. 2006). While neuronal death is important and could contribute to the decline in cognition, synapse loss is the best correlate with the severity of dementia in AD (Davies et al. 1987;Terry et al. 1991). However, this loss Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Koenig and Ikeda 1989). Collectively, these...

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Section: Discussionmentioning

confidence: 99%

Beta-amyloid disrupted synaptic vesicle endocytosis in cultured hippocampal neurons

Kelly¹,

Ferreira²

2007

Neuroscience

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“…CaMKII/JNK and calcineurin/NFAT-induced up-regulation of Fas/FasL is involved in cell apoptosis (40,41). In addition, activated calcineurin may be involved in the endocytosis of kainate receptors through the dephosphorylation of endocytic proteins such as amphiphysin I and dynamin I (42,43). In our experiments, kainate-evoked [Ca 2+ ] i and reduced membrane expression of GluK2 were observed simultaneously; therefore, we speculate that Ca 2+ /calmodulinactivated calcineurin may induce kainate receptor endocytosis.…”

Section: Discussionmentioning

confidence: 99%

Tyrosine phosphorylation of GluK2 up-regulates kainate receptor-mediated responses and downstream signaling after brain ischemia

Zhu

Kong

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Although kainate receptors play important roles in ischemic stroke, the molecular mechanisms underlying postischemic regulation of kainate receptors remain unclear. In this study we demonstrate that Src family kinases contribute to the potentiation of kainate receptor function. Brain ischemia and reperfusion induce rapid and sustained phosphorylation of the kainate receptor subunit GluK2 by Src in the rat hippocampus, implicating a critical role for Src-mediated GluK2 phosphorylation in ischemic brain injury. The NMDA and kainate receptors are involved in the tyrosine phosphorylation of GluK2. GluK2 binds to Src, and the tyrosine residue at position 590 (Y590) on GluK2 is a major site of phosphorylation by Src kinases. GluK2 phosphorylation at Y590 is responsible for increases in whole-cell currents and calcium influx in response to transient kainate stimulation. In addition, GluK2 phosphorylation at Y590 facilitates the endocytosis of GluK2 subunits, and the activation of JNK3 and its substrate c-Jun after long-term kainate treatment. Thus, Src phosphorylation of GluK2 plays an important role in the opening of kainate receptor channels and downstream proapoptosis signaling after brain ischemia. The present study reveals an additional mechanism for the regulation of GluK2-containing kainate receptors by Src family kinases, which may be of pathological significance in ischemic stroke.K ainate receptors are widely expressed in the mammalian central nervous system, particularly in the hippocampus, where they are involved in synaptic transmission (1), neuronal plasticity (2), and excitotoxic lesions (3). Overactivation of postsynaptic kainate receptor-mediated responses is associated with neurological disorders resulting from ischemic stroke (4). However, the intracellular processes responsible for the postischemic up-regulation of kainate receptors, and its molecular consequences, have not yet been elucidated.Reversible phosphorylation is one of the most common mechanisms regulating the function of receptor proteins. In particular, serine/threonine phosphorylation is important in the functional regulation of NMDA (5), AMPA (6), and kainate receptors (6-9), with tyrosine phosphorylation of NMDA receptors the most extensively studied (10, 11). There is accumulating evidence to show that tyrosine phosphorylation of NMDA receptors modulates their assembly at synapses after brain ischemia (12-15). However, less is known about the regulation of kainate receptor activity by tyrosine phosphorylation. Src is an important member of Src family kinases, the largest family of nonreceptor protein tyrosine kinases, and is highly expressed in the brain. Brain ischemia increases Src kinase activity in vulnerable brain regions, including the hippocampus (15-18), but it is not known whether Src phosphorylates kainate receptors.Kainate receptors are tetrameric glutamate-gated ion channels consisting of GluK1-GluK5 subunits, formerly known as GluR5-GluR7, KA1, and KA2, respectively. Functional kainate receptors can be expressed as homo...

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“…[2][3][4][5][6] Unlike other cell cycle-promoting members of Cdk family, Cdk5 kinase primarily modulates neuroskeletal dynamics in postmitotic neurons. 3,7,8 Cdk5 plays an essential role in both developing and adult neurons, including neuronal migration, 9,10 axon guidance, 11 neurite outgrowth, 7 dynamics of synaptic structure, [12][13][14] neurotransmission, 15,16 and neuronal secretion. 17 Cdk5 null mice suffer perinatal mortality, with severe defects in neuronal migration and laminar configuration in the cerebral cortex.…”

Section: Introductionmentioning

confidence: 99%

p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death

Lin

Zakeri

2005

Cell Death Differ

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Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclindependent kinase family that is mostly seen in neurons, does not vary with cell cycle, and is activated in many neurodegenerative disorders and other non-neuronal pathologies, but its relationship to non-neuronal apoptosis is not understood, nor is the control of the activation of Cdk5 by its activators. The most widely studied activator of Cdk5, p35, is cleaved to p25 by calpain, an event that has been linked with activation of Cdk5 and neuronal death. Here we report that calpain-mediated Cdk5/p25 activation accompanies nonneuronal as well as neuronal cell death, suggesting that the p35/calpain/p25/Cdk5 activation sequence is a general feature of cell death. We further demonstrate that Cdk5 can be activated in the absence of p53, Apaf-1, caspase-9, and -3 during cell death, indicating that its activation relates more to cell death than to a specific pathway of apoptosis.

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Cophosphorylation of amphiphysin I and dynamin I by Cdk5 regulates clathrin-mediated endocytosis of synaptic vesicles

Cited by 180 publications

References 36 publications

Beta-amyloid disrupted synaptic vesicle endocytosis in cultured hippocampal neurons

Beta-amyloid disrupted synaptic vesicle endocytosis in cultured hippocampal neurons

Tyrosine phosphorylation of GluK2 up-regulates kainate receptor-mediated responses and downstream signaling after brain ischemia

p53, Apaf-1, caspase-3, and -9 are dispensable for Cdk5 activation during cell death

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