Hendrika M.A. VanDongen's research while affiliated with Duke-NUS Medical School and other places

Publications (21)

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Chromatin modification is an important epigenetic mechanism underlying neuroplasticity. Histone methylation and acetylation have both been shown to modulate gene expression, but the machinery responsible for mediating these changes in neurons has remained elusive. Here we identify a chromatin-modifying complex containing the histone demethylase PHF...
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Arc is an immediate-early gene whose genetic ablation selectively abrogates long-term memory, indicating a critical role in memory consolidation. Although Arc protein localizes to neuronal synapses, it also localizes to the neuronal nucleus, where its function is less understood. Nuclear Arc forms a complex with the β-spectrin isoform βSpIVΣ5 and a...
Article
Introduction: N-methyl-D-aspartate (NMDA) receptors are glutamate-gated ion channels that play key roles in processes underlying learning and memory. NMDA receptor dysfunction is thought to contribute to virtually every major neurological disorder, including Alzheimer's, Parkinson's, and Huntington's disease, stroke, epilepsy, neuropathic pain, sch...
Article
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Arc/Arg3.1 is an immediate early gene whose expression is necessary for the late-phase of long-term potentiation (LTP) and memory consolidation. Whereas pathways regulating Arc transcription have been extensively investigated, less is known about the role of post-transcriptional mechanisms in Arc expression. Fluorescence microscopy experiments in c...
Article
Activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) is an immediate early gene, whose expression in the central nervous system is induced by specific patterns of synaptic activity. Arc is required for the late-phase of long-term potentiation (LTP) and memory consolidation, and has been implicated in AMPA receptor trafficking. Since Arc'...
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Abnormalities in dendritic spines have long been associated with cognitive dysfunction and neurodevelopmental delay, whereas rapid changes in spine shape underlie synaptic plasticity. The key regulators of cytoskeletal reorganization in dendrites and spines are the Rho GTPases, which modify actin polymerization in response to synaptic signaling. Rh...
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Maintenance of synaptic plasticity requires protein translation. Because changes in synaptic strength are regulated at the level of individual synapses, a mechanism is required for newly translated proteins to specifically and persistently modify only a subset of synapses. Evidence suggests this may be accomplished through local translation of prot...
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The interaction of an agonist with its receptor can be characterized by two fundamental properties, affinity and efficacy. Affinity defines how tightly the agonist associates with its receptor, and efficacy measures the ability of the bound ligand to activate the receptor. Although affinity and efficacy are independent properties, the binding and a...
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Protein transport to and from the postsynaptic plasma membrane is thought to be of central importance for synaptic plasticity. However, the molecular details of such processes are poorly understood. One mechanism by which membrane and secretory proteins may be transported to and from postsynaptic membranes is via cargo receptors. We studied the den...
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Spinophilin/neurabin II is an actin-associated scaffolding protein enriched in the dendritic spines of neurons. Previously, the actin-binding domain (ABD) of spinophilin was localized to a domain between amino acids (aa) 1 and 154. In a mass spectrometry screen for spinophilin-binding proteins, we have identified an additional actin-binding region...
Article
Because NMDA receptors play critical roles in both neuronal survival and plasticity, their expression levels need to be carefully controlled. The number of functional NMDA receptors is temporally and spatially regulated at a hierarchy of levels, from gene transcription to protein trafficking. In this review we will focus on mechanisms for controlli...
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Ion channels alternate stochastically between two functional states, open and closed. This gating behavior is controlled by membrane potential or by the binding of neurotransmitters in voltage- and ligand-gated channels, respectively. Although much progress has been made in defining the structure and function of the ligand-binding cores and the vol...
Article
Abl-interactor (Abi) proteins are targets of Abl-family nonreceptor tyrosine kinases and are required for Rac-dependent cytoskeletal reorganization in response to growth factor stimulation. We asked if the expression, phosphorylation, and cellular localization of Abi-1 and Abi-2 supports a role for these proteins in Abl signaling in the developing...
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Alanine 714 of the NMDA receptor NR1 subunit resides in the glycine binding pocket. The Ala714Leu mutation substantially shifts glycine affinity, but here no effect on antagonism by DCK is detected. Ala714Leu is also found to limit the efficacy of a partial agonist without altering its apparent affinity. The differential sensitivity of Ala714Leu to...
Article
Glutamate receptors are large integral membrane proteins that belong to the class of ligand-gated ion channels. They constitute a family of receptors that are activated by binding of the neurotransmitter l-glutamate. Functional receptors are formed by assembly of several subunits around a central ion-conducting pore. Each subunit is thought to cont...
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While attempting to map a central region in the M3-M4 linker of the N-methyl-D-aspartate receptor NR1 subunit, we found that mutation of a single position, Ala-714, greatly reduced the apparent affinity for glycine. Proximal N-glycosylation localized this region to the extracellular space. Glycine affinities of additional Ala-714 mutations correlat...
Article
Ion permeation and channel opening are two fundamental properties of ion channels, the molecular bases of which are poorly understood. Channels can exist in two permeability states, open and closed. The relative amount of time a channel spends in the open conformation depends on the state of activation. In voltage-gated ion channels, activation inv...
Article
The pore of potassium channels is lined by four identical, highly conserved hairpin loops, symmetrically arranged around a central permeation pathway. Introduction of cysteines into the external mouth of the drk1 K channel pore resulted in the formation of disulfide bonds that were incompatible with channel function. Breaking these bonds restored f...
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Full-text available
The N-methyl-D-aspartate (NMDA) receptor plays a central role in such phenomena as long term potentiation and excitotoxicity. This importance in defining both function and viability suggests that neurons must carefully control their expression of NMDA receptors. Whereas the NR1 subunit of the NMDA receptor is ubiquitously transcribed throughout the...
Article
Full-text available
The N-methyl-D-aspartate (NMDA) receptor plays a central role in such phenomena as long term potentiation and excitotoxicity. This importance in defining both function and viability suggests that neurons must carefully control their expression of NMDA receptors. Whereas the NR1 subunit of the NMDA receptor is ubiquitously transcribed throughout the...
Article
Single channel recordings demonstrate that ion channels switch stochastically between an open and a closed pore conformation. In search of a structural explanation for this universal open/close behavior, we have uncovered a striking degree of amino acid homology across the pore-forming regions of voltage-gated K channels and glutamate receptors. Th...

Citations

... NR2 expression may be the rate-limiting step in functional NMDA receptor expression [28]. Therefore, changes of subunit NR2A or NR2B could modulate overall NMDA receptor activity [29] and contribute to the formation of new NMDA receptors with distinct functional characteristics [30]. ...
... Dendritic spines play vital roles in the formation and maintenance of emotional circuits and synaptic plasticity and cognition (Lin et al., 2012;Oey et al., 2015). The dendritic spine structure was determined using the Golgi apparatus to stain the hippocampus and identified a significant reduction of dendritic spines in the D(+)Galactose group and the L-PWSI group when compared with the control (p < 0.001), and a significant reduction in the L-PWSI and D(+)Galactose-treated group when compared with only L-PWSI or D(+)Galactose-treated groups (p < 0.01) as showed in Figures 5C,D [F (3 , 9) = 56.25, ...
... Interestingly, our finding of a quasi-complete sequestration of unmodifiable S67A Arc suggests that phosphorylation at this specific site is required for the release of Arc from its nuclear interactors to then allow export. Known nuclear molecular interactions of Arc include the formation of a complex composed of the β-spectrin isoform βSpIVΣ5, promyelocytic leukemia (PML) bodies, and acetyltransferase Tip60 that organize to increase acetylation of histone 4 at lysine 12 (Bloomer et al., 2007;Wee et al. 2014). ...
... The homologous proteins used as templates for modeling NMDARs are structures of an AMPAR [12], a closely related and highly homologous iGluR, and of the NaK channel [13]. The NaK channel is a tetrameric non-selective cation channel closely related to potassium channels, which share a moderate degree of sequence similarity but highly similar secondary, tertiary, and quaternary structure with iGluR TMDs [33][34][35]. Use of two homologous structures to model NMDARs was important because in AMPAR structures, some of the TMD, in particular the extended region of the pore loop, were not fully resolved. Pore loops were well-resolved, however, in a number of structures of the more distantly related tetrameric channels, including the NaK channel. ...
... Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS) and exerts a physiological role by binding to several glutamate receptors. Of the various glutamate receptors, NMDA receptors have received more attention due to their pivotal role in axonal formation, long-term potentiation, and excitotoxicity [3,4]. Studies have shown that NMDA receptors are closely related to learning and memory [5]. ...
... structure therefore does not account for the enhanced rate of disulfide bond formation by Cys 376 in the C-type inactivated state. Similarly, the change in the C-C distance of the 377 side chains in these structures is 0.51 Å (14.06 to 13.55 Å), and this distance is still longer than expected for the formation of a metal coordination site by the Cys 377 side chains from adjacent subunits (33). The K v 1.2-2.1-3m ...
... Having established that glycine-primed internalization was recapitulated with recombinant NMDARs, we mutated residues in the ligand-binding domain of GluN1 to test the hypothesis that glycine priming depends upon glycine binding to this subunit. We first used a GluN1 mutant carrying four amino acid substitutions, N710R, Y711R, E712A, A714L, which impaired but did not abolish gating of NMDARs containing this GluN1 mutation [27,28]. We found that NMDARs with this quadruple GluN1 mutation, which we refer to as the RRAL mutant, were expressed at levels comparable to those of wildtype GluN1 when co-transfected with GluN2B, but there was no detectable expression if co-transfected with GluN2A (data not shown). ...
... We used the whole-cell Kv2.1 G-V relationship as a proxy for Kv2.1 open probability. Although the occurrence of subconducting conformations of rat Kv2.1 single channels (Chapman et al., 1997) makes the G-V relationship an imperfect proxy, the fully conducting conformation of a rat Kv2.1 variant has been used to effectively characterize its G-V relationship (Islas and Sigworth, 1999), and we have found subconducting conformations to occur <10% as often as full openings in this Kv2.1-CHO cell line (Tilley et al., 2019), suggesting that the G-V relationship is reasonably proportionate to open probability. ...
... Having established that glycine-primed internalization was recapitulated with recombinant NMDARs, we mutated residues in the ligand-binding domain of GluN1 to test the hypothesis that glycine priming depends upon glycine binding to this subunit. We first used a GluN1 mutant carrying four amino acid substitutions, N710R, Y711R, E712A, A714L, which impaired but did not abolish gating of NMDARs containing this GluN1 mutation [27,28]. We found that NMDARs with this quadruple GluN1 mutation, which we refer to as the RRAL mutant, were expressed at levels comparable to those of wildtype GluN1 when co-transfected with GluN2B, but there was no detectable expression if co-transfected with GluN2A (data not shown). ...
... Overall, this would suggest that loss of Abi3-Gngt2 function leads to early induction of immunity that could lead to detrimental outcomes in the longer term (Fig. 11). It is known that phosphorylation is key to maintaining the stability and function of ABI family of proteins [37,80]. Thus, our data suggests that the AD-associated mutation could result in hypomorphic function or partial loss of function. ...