A primate-specific short GluN2A-NMDA receptor isoform is expressed in the human brain

Warming, Hannah; Pegasiou, Chrysia-Maria; Pitera, Aleksandra P.; Kariis, Hanna; Houghton, Steven D.; Kurbatskaya, Ksenia; Ahmed, Aminul I.; Grundy, Paul; Vajramani, Girish; Bulters, Diederik; Altafaj, Xavier; Deinhardt, Katrin; Vargas‐Caballero, Mariana

doi:10.1186/s13041-019-0485-9

Cited by 16 publications

(11 citation statements)

References 28 publications

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“…We detected the GluN2A-short splice junction with similar frequencies in chimpanzee and macaque datasets (Fig. S20B), but the corresponding splice sites are absent in rat and mouse, which supports the suggestion that this is a primate-specific isoform [139]. Shortening of the GluN2A CTD should have important functional consequences, as it results in a loss of several interaction motifs, including CaMKII and PSD-95 binding sites [27,122].…”

Section: Alternative Splicing Of Delta Receptor Subunitssupporting

confidence: 79%

“…S20). The same isoform, named GluN2A-short, was recently reported by Warming et al to be expressed in human brain and to form functional receptors upon coexpression with GluN1 [139]. Our junction analysis shows that the GluN2A-short isoform is abundantly expressed in human brain (global abundance 25%), in some datasets even on par with the canonical isoform (Fig.…”

Section: Alternative Splicing Of Delta Receptor Subunitssupporting

confidence: 75%

“…S15 and S23B). In contrast, the identified GluN2A-short (see also [139]) and GluN2C-b isoforms appear to be primate-specific (Figs. S20 and S22).…”

Section: Discussionmentioning

confidence: 96%

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Splicing and editing of ionotropic glutamate receptors: a comprehensive analysis based on human RNA-Seq data

Herbrechter

Hube

Buchholz

et al. 2021

Cell. Mol. Life Sci.

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Ionotropic glutamate receptors (iGluRs) play key roles for signaling in the central nervous system. Alternative splicing and RNA editing are well-known mechanisms to increase iGluR diversity and to provide context-dependent regulation. Earlier work on isoform identification has focused on the analysis of cloned transcripts, mostly from rodents. We here set out to obtain a systematic overview of iGluR splicing and editing in human brain based on RNA-Seq data. Using data from two large-scale transcriptome studies, we established a workflow for the de novo identification and quantification of alternative splice and editing events. We detected all canonical iGluR splice junctions, assessed the abundance of alternative events described in the literature, and identified new splice events in AMPA, kainate, delta, and NMDA receptor subunits. Notable events include an abundant transcript encoding the GluA4 amino-terminal domain, GluA4-ATD, a novel C-terminal GluD1 (delta receptor 1) isoform, GluD1-b, and potentially new GluK4 and GluN2C isoforms. C-terminal GluN1 splicing may be controlled by inclusion of a cassette exon, which shows preference for one of the two acceptor sites in the last exon. Moreover, we identified alternative untranslated regions (UTRs) and species-specific differences in splicing. In contrast, editing in exonic iGluR regions appears to be mostly limited to ten previously described sites, two of which result in silent amino acid changes. Coupling of proximal editing/editing and editing/splice events occurs to variable degree. Overall, this analysis provides the first inventory of alternative splicing and editing in human brain iGluRs and provides the impetus for further transcriptome-based and functional investigations.

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Section: Alternative Splicing Of Delta Receptor Subunitssupporting

confidence: 79%

Section: Alternative Splicing Of Delta Receptor Subunitssupporting

confidence: 75%

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Splicing and editing of ionotropic glutamate receptors: a comprehensive analysis based on human RNA-Seq data

Herbrechter

Hube

Buchholz

et al. 2021

Cell. Mol. Life Sci.

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“…Glutamate-gated receptors of the NMDA subtype require intracellular depolarisation to relieve voltage-dependent extracellular Mg 2+ block of the ion channel pore. Once opened, NMDAR channels can allow Ca 2+ influx which triggers the synaptic short primate-specific GluN2A isoform (GluN2A-S) forms functional NMDAR together with GluN1 and accounts for one third of the total GluN2A protein in adult human cortex as recently described by us (Warming et al, 2019).…”

Section: Introductionmentioning

confidence: 87%

Age-Dependent Changes in Synaptic NMDA Receptor Composition in Adult Human Cortical Neurons

et al. 2020

Self Cite

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The molecular processes underlying the aging-related decline in cognitive performance and memory observed in humans are poorly understood. Studies in rodents have shown a decrease in N-methyl-D-aspartate receptors (NMDARs) that contain the GluN2B subunit in aging synapses, and this decrease is correlated with impaired memory functions. However, the age-dependent contribution of GluN2B-containing receptors to synaptic transmission in human cortical synapses has not been previously studied. We investigated the synaptic contribution of GluN2A and GluN2B-containing NMDARs in adult human neurons using fresh nonpathological temporal cortical tissue resected during neurosurgical procedures. The tissue we obtained fulfilled quality criteria by the absence of inflammation markers and proteomic degradation. We show an age-dependent decline in the NMDA/AMPA receptor ratio in adult human temporal cortical synapses. We demonstrate that GluN2B-containing NMDA receptors contribute to synaptic responses in the adult human brain with a reduced contribution in older individuals. With previous evidence demonstrating the critical role of synaptic GluN2B in regulating synaptic strength and memory storage in mice, this progressive reduction of GluN2B in the human brain during aging may underlie a molecular mechanism in the age-related decline in cognitive abilities and memory observed in humans.

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“…Understanding the functioning of human neurons is highly relevant, because findings in experimental animals do not always translate to human. In fact, analogous neuronal types between the human and rodent cortex exhibit various between-species differences in their physiological functional parameters 9, 13, 14, 15, 16, 17, 18, 19, 20, 21 . Species-specific behaviors may hence arise from even small differences in neuronal types and neuronal circuits 22, 23 , making it critical to uncover the “uniqueness” of the human neurons and to investigate its outcome on the operation of anatomically identified neuronal circuits.…”

Section: Introductionmentioning

confidence: 99%

Somatic HCN channels augment and speed up GABAergic basket cell input-output function in human neocortex

Szegedi

Bakos

Furdan

et al. 2021

Preprint

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Neurons in the mammalian brain exhibit evolution-driven species-specific differences in their functional properties. Therefore, understanding the human brain requires unraveling the human neuron 'uniqueness' and how it contributes to the operation of specific neuronal circuits. We show here that a highly abundant type of inhibitory neurons in the neocortex, GABAergic parvalbumin-expressing basket cell (pv+BC), exhibits in the human brain a specific somatic leak current mechanism, which is absent in their rodent neuronal counterparts. Human pv+BC soma shows electric leak conductance mediated by hyperpolarization-activated cyclic nucleotide-gated channels. This leak conductance has depolarizing effects on the resting membrane potential and it accelerates the rise of synaptic potentials in the cell soma. The leak facilitates the human pv+BC input-to-output fidelity and shortens the action potential generation to excitatory inputs. This mechanism constitutes an adaptation that enhances signal transmission fidelity and speed in the common inhibitory circuit in the human but not in the rodent neocortex.

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A primate-specific short GluN2A-NMDA receptor isoform is expressed in the human brain

Cited by 16 publications

References 28 publications

Splicing and editing of ionotropic glutamate receptors: a comprehensive analysis based on human RNA-Seq data

Splicing and editing of ionotropic glutamate receptors: a comprehensive analysis based on human RNA-Seq data

Age-Dependent Changes in Synaptic NMDA Receptor Composition in Adult Human Cortical Neurons

Somatic HCN channels augment and speed up GABAergic basket cell input-output function in human neocortex

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