Regulation of synaptic structure and function by palmitoylated AMPA receptor binding protein

Misra, Charu; Restituito, Sophie; Ferreira, José Luiz P.; Rameau, Gerald A.; Fu, Jie; Ziff, Edward B.

doi:10.1016/j.mcn.2010.01.001

Cited by 26 publications

(27 citation statements)

References 60 publications

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“…Moreover, DHHC5 targets GRIP1bwt, but not the palmitoylation mutant GRIP1b-C11S, to similar dendritic puncta. Notably, though, the endosomal targeting of palmitoylated GRIP1b is distinct from the synaptic targeting described for the closely related palmitoylated GRIP2b (DeSouza et al, 2002; Misra et al, 2010). Consistent with these reports, we also observed prominent GRIP2b targeting to dendritic spines, which did not require DHHC5 or DHHC8 co-expression (not shown).…”

Section: Discussionmentioning

confidence: 76%

Palmitoylation by DHHC5/8 Targets GRIP1 to Dendritic Endosomes to Regulate AMPA-R Trafficking

Thomas

Hayashi

Chiu

et al. 2012

Neuron

166

293

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Summary Palmitoylation, a key regulatory mechanism controlling protein targeting, is catalyzed by DHHC-family palmitoyl acyltransferases (PATs). Impaired PAT activity is linked to several neurodevelopmental and neuropsychiatric disorders, suggesting critical roles for palmitoylation in neuronal function. However, few substrates for specific PATs are known, and functional consequences of specific palmitoylation events are frequently uncharacterized. Here, we identify two related PATs, DHHC5 and DHHC8, as specific regulators of the PDZ domain protein GRIP1b. Binding, palmitoylation and dendritic targeting of GRIP1b require a DHHC5/8 PDZ ligand that is absent in all other PATs. Palmitoylated GRIP1b is targeted to trafficking endosomes, and may link endosomes to kinesin motors. Consistent with this trafficking role, GRIP1b's palmitoylation turnover rate approaches the highest of all reported proteins, and palmitoylation increases GRIP1b's ability to accelerate AMPA-R recycling. These findings identify the first neuronal DHHC5/8 substrate, define novel mechanisms controlling palmitoylation specificity, and suggest further links between dysregulated palmitoylation and neurodevelopmental / neuropsychiatric conditions.

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Section: Discussionmentioning

confidence: 76%

Palmitoylation by DHHC5/8 Targets GRIP1 to Dendritic Endosomes to Regulate AMPA-R Trafficking

Thomas

Hayashi

Chiu

et al. 2012

Neuron

166

293

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“…The spines facilitate throughput of the excitatory signal to the dendritic trunk while at the same time constraining features, such as local calcium influx, to mediate synapse-specific effects (Fiala et al, 1998; Yuste et al, 1999; Sheng and Hoogenraad, 2007; Yuste, 2011). Numerous molecular mechanisms have been shown to promote the formation, localization, and stabilization of dendritic spines (Tolias et al, 2005; Xie et al, 2007; Tran et al, 2009; Lai and Ip, 2009; Han et al, 2010; Misra et al, 2010). Recently it has been reported that adult mice lacking a major class of nicotinic acetylcholine receptors (nAChRs), namely β2-containing heteropentameric receptors (β2*-nAChRs), have altered numbers of dendritic spines in a variety of cortical regions in brain (Ballesteros-Yanez et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Induction of Dendritic Spines by 2-Containing Nicotinic Receptors

Lozada

Wang²,

Gounko³

et al. 2012

Journal of Neuroscience

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Glutamatergic synapses are located mostly on dendritic spines in the adult nervous system. The spines serve as postsynaptic compartments, containing components that mediate and control the synaptic signal. Early in development, when glutamatergic synapses are initially forming, waves of excitatory activity pass through many parts of the nervous system and are driven in part by a class of heteropentameric β2-containing nicotinic acetylcholine receptors (β2*-nAChRs). These β2*-nAChRs are widely distributed and, when activated, can depolarize the membrane and elevate intracellular calcium levels in neurons. We show here that β2*-nAChRs are essential for acquisition of normal numbers of dendritic spines during development. Mice constitutively lacking the β2-nAChR gene have fewer dendritic spines than do age-matched wild-type mice at all times examined. Activation of β2*-nAChRs by nicotine either in vivo or in organotypic slice culture quickly elevates the number of spines. RNA interference studies both in vivo and in organotypic culture demonstrate that the β2*-nAChRs act in a cell-autonomous manner to increase the number of spines. The increase depends on intracellular calcium and activation of calcium, camodulin-dependent protein kinase II. Absence of β2*-nAChRs in vivo causes a disproportionate number of glutamatergic synapses to be localized on dendritic shafts, rather than on spines as occurs in wild-type. This shift in synapse location is found both in the hippocampus and cortex, indicating the breadth of the effect. Because spine synapses differ from shaft synapses in their signaling capabilities, the shift observed is likely to have significant consequences for network function.

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“…The GluR1 surface levels were increased in the presence of phospho-deficient δ-catenin. Although δ-catenin is not associated with GluR1 at its PDZ-binding domain by interaction with GRIP/ABP, it has been reported previously that heteromerization of GluR1/2 may be responsible for increased surface GluR1 with upregulation of GluR2 surface expression (Misra et al, 2010). It would also be interesting to determine whether the other AMPA receptors GluR3 and GluR4 are affected by this phenomenon as a result of heteromerization with GluR2.…”

Section: Discussionmentioning

confidence: 99%

Cdk5-Mediated Phosphorylation of -Catenin Regulates Its Localization and GluR2-Mediated Synaptic Activity

Poore

Sundaram²,

Pareek³

et al. 2010

Journal of Neuroscience

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Cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation plays an important role in proper synaptic function and transmission. Loss of Cdk5 activity results in abnormal development of the nervous system accompanied by massive disruptions in cortical migration and lamination, therefore impacting synaptic activity. The Cdk5 activator p35 associates with ␦-catenin, the synaptic adherens junction protein that serves as part of the anchorage complex of AMPA receptor at the postsynaptic membrane. However, the implications of Cdk5-mediated phosphorylation of ␦-catenin have not been fully elucidated. Here we show that Cdk5-mediated phosphorylation of ␦-catenin regulates its subcellular localization accompanied by changes in dendritic morphogenesis and synaptic activity. We identified two Cdk5 phosphorylation sites in mouse ␦-catenin, serines 300 and 357, and report that loss of Cdk5 phosphorylation of ␦-catenin increased its localization to the membrane. Furthermore, mutations of the serines 300 and 357 to alanines to mimic nonphosphorylated ␦-catenin resulted in increased dendritic protrusions accompanied by increased AMPA receptor subunit GluR2 localization at the membrane. Consistent with these observations, loss of Cdk5 phosphorylation of ␦-catenin increased the AMPA/NMDA ratio. This study reveals how Cdk5 phosphorylation of the synaptic mediator protein ␦-catenin can alter its localization at the synapse to impact neuronal synaptic activity.

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Regulation of synaptic structure and function by palmitoylated AMPA receptor binding protein

Cited by 26 publications

References 60 publications

Palmitoylation by DHHC5/8 Targets GRIP1 to Dendritic Endosomes to Regulate AMPA-R Trafficking

Palmitoylation by DHHC5/8 Targets GRIP1 to Dendritic Endosomes to Regulate AMPA-R Trafficking

Induction of Dendritic Spines by 2-Containing Nicotinic Receptors

Cdk5-Mediated Phosphorylation of -Catenin Regulates Its Localization and GluR2-Mediated Synaptic Activity

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