Structure and symmetry inform gating principles of ionotropic glutamate receptors

Zhu, Shujia; Gouaux, Eric

doi:10.1016/j.neuropharm.2016.08.034

Cited by 67 publications

(48 citation statements)

References 31 publications

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“…For example, receptors and ion channels that until then were theoretical constructs became real, allowing us to understand, in molecular terms, fundamental neuronal properties, such as action potentials and neurotransmitter and neuropeptide receptors (Catterall et al, 2017; Zhu and Gouaux, 2017). Transcription factors that dictate neural identity were also defined (Arlotta and Hobert, 2015: Jessell, 2000) and fundamental mechanisms of axon guidance were described (Tessier-Lavigne, 2002); and the mechanism by which Ca 2+ -influx into a nerve terminal triggers neurotransmitter release within a few hundred microseconds was largely solved (Südhof, 2013).…”

Section: Many Fundamental Questions Remain Unaddressedmentioning

confidence: 99%

Molecular Neuroscience in the 21st Century: A Personal Perspective

Südhof

2017

Neuron

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Neuroscience is inherently interdisciplinary in its quest to explain the brain. Like all biological structures the brain operates at multiple levels, from nano-scale molecules to meter-scale systems. Here, I argue that understanding the nano-scale organization of the brain is not only helpful for insight into its function, but is actually a requisite for such insight. I propose that one impediment to a better understanding of the brain is that most of its molecular processes are incompletely understood, and suggest a number of key questions that require our attention for further progress in neuroscience to be achieved beyond a description of the activity of circuits.

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Section: Many Fundamental Questions Remain Unaddressedmentioning

confidence: 99%

Molecular Neuroscience in the 21st Century: A Personal Perspective

Südhof

2017

Neuron

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“…As we have known, glutamate, a major excitatory neurotransmitter, induces astrocytes excitability associated with the increase in the intracellular concentration of calcium ions ([Ca 2+ ] i ) partly through activation of ionotropic glutamate receptors (iGluRs). The iGluRs contain the N‐methyl‐ d ‐aspartate (NMDA), the α‐amino‐3‐(5‐methyl‐3‐oxo‐1, 2‐oxazol‐4‐yl) propanoic acid (AMPA), and the kainate (KA) receptors (Zhu & Gouaux, ). The AMPA receptors consist of four subunits: GluA1–GluA4 (formerly named as GluR1–GluR4) (Traynelis et al, ).…”

Section: Introductionmentioning

confidence: 99%

Vascular endothelial growth factor increases the function of calcium‐impermeable AMPA receptor GluA2 subunit in astrocytes via activation of protein kinase C signaling pathway

Kou

et al. 2019

Glia

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Astrocytic calcium signaling plays pivotal roles in the maintenance of neural functions and neurovascular coupling in the brain. Vascular endothelial growth factor (VEGF), an original biological substance of vessels, regulates the movement of calcium and potassium ions across neuronal membrane. In this study, we investigated whether and how VEGF regulates glutamate‐induced calcium influx in astrocytes. We used cultured astrocytes combined with living cell imaging to detect the calcium influx induced by glutamate. We found that VEGF quickly inhibited the glutamate/hypoxia‐induced calcium influx, which was blocked by an AMPA receptor antagonist CNQX, but not D‐AP5 or UBP310, NMDA and kainate receptor antagonist, respectively. VEGF increased phosphorylation of PKCα and AMPA receptor subunit GluA2 in astrocytes, and these effects were diminished by SU1498 or calphostin C, a PKC inhibitor. With the pHluorin assay, we observed that VEGF significantly increased membrane insertion and expression of GluA2, but not GluA1, in astrocytes. Moreover, siRNA‐produced knockdown of GluA2 expression in astrocytes reversed the inhibitory effect of VEGF on glutamate‐induced calcium influx. Together, our results suggest that VEGF reduces glutamate‐induced calcium influx in astrocytes via enhancing PKCα‐mediated GluA2 phosphorylation, which in turn promotes the membrane insertion and expression of GluA2 and causes AMPA receptors to switch from calcium‐permeable to calcium‐impermeable receptors, thereby inhibiting astrocytic calcium influx. The present study reveals that excitatory neurotransmitter glutamate‐mediated astrocytic calcium influx can be regulated by vascular biological factor via activation of AMPA receptor GluA2 subunit and uncovers a novel coupling mechanism between astrocytes and endothelial cells within the neurovascular unit.

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“…The ionotropic glutamate receptor family includes three receptor subtypes that can all be activated upon binding of glutamate: ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors (1)(2)(3). Compared with NMDA receptors, AMPA and kainate receptors are more alike in both sequence and structure (3,4). AMPA receptors are expressed post-synaptically and are involved in fast excitatory neurotransmission (1).…”

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confidence: 99%

Identification and characterization of RNA aptamers: A long aptamer blocks the AMPA receptor and a short aptamer blocks both AMPA and kainate receptors

Jaremko

Huang

Wen

et al. 2017

Journal of Biological Chemistry

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AMPA and kainate receptors, along with NMDA receptors, represent different subtypes of glutamate ion channels. AMPA and kainate receptors share a high degree of sequence and structural similarities, and excessive activity of these receptors has been implicated in neurological diseases such as epilepsy. Therefore, blocking detrimental activity of both receptor types could be therapeutically beneficial. Here, we report the use of an in vitro evolution approach involving systematic evolution of ligands by exponential enrichment with a single AMPA receptor target (i.e. GluA1/2R) to isolate RNA aptamers that can potentially inhibit both AMPA and kainate receptors. A full-length or 101-nucleotide (nt) aptamer selectively inhibited GluA1/2R with a K I of ϳ5 M, along with GluA1 and GluA2 AMPA receptor subunits. Of note, its shorter version (55 nt) inhibited both AMPA and kainate receptors. In particular, this shorter aptamer blocked equally potently the activity of both the GluK1 and GluK2 kainate receptors. Using homologous binding and whole-cell recording assays, we found that an RNA aptamer most likely binds to the receptor's regulatory site and inhibits it noncompetitively. Our results suggest the potential of using a single receptor target to develop RNA aptamers with dual activity for effectively blocking both AMPA and kainate receptors.Ionotropic glutamate receptors mediate the majority of excitatory neurotransmission in the mammalian central nervous system (CNS) and are indispensable for brain development and function (1, 2). The ionotropic glutamate receptor family includes three receptor subtypes that can all be activated upon binding of glutamate: ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors (1-3). Compared with NMDA receptors, AMPA and kainate receptors are more alike in both sequence and structure (3, 4). AMPA receptors are expressed post-synaptically and are involved in fast excitatory neurotransmission (1). Kainate receptors are expressed both pre-and post-synaptically, and contribute to excitatory neurotransmission and modulate network excitability by regulating neurotransmitter release (5, 6).AMPA and kainate receptors are widely expressed in the brain. AMPA receptors have four subunits, i.e. GluA1-4. GluA1-3 are enriched in the hippocampus, outer layers of the cortex, olfactory regions, lateral septum, basal ganglia, and amygdala, etc. (7,8). The expression of the GluA4 subunit is low to moderate throughout the CNS, except in the reticular thalamic nuclei and the cerebellum where its level is high (9 -11). Kainate receptors have five subunits, i.e. GluK1-5. At the mRNA level, GluK1 is highly abundant in the neocortex, hypothalamus, and the hindbrain, whereas GluK2 is highly abundant in the cerebellum. GluK3 is widely distributed in the brain. GluK4 is enriched in the hippocampus (CA3 pyramidal cells).GluK5 is abundant in the neocortex, hippocampus (dentate gyrus and CA2, 3 pyramidal cells), and cerebellum (granule cells) (12,13). At the pro...

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Structure and symmetry inform gating principles of ionotropic glutamate receptors

Cited by 67 publications

References 31 publications

Molecular Neuroscience in the 21st Century: A Personal Perspective

Molecular Neuroscience in the 21st Century: A Personal Perspective

Vascular endothelial growth factor increases the function of calcium‐impermeable AMPA receptor GluA2 subunit in astrocytes via activation of protein kinase C signaling pathway

Identification and characterization of RNA aptamers: A long aptamer blocks the AMPA receptor and a short aptamer blocks both AMPA and kainate receptors

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