Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

Pharmacological Reviews, Год журнала: 2021, Номер 73(4), С. 1469 - 1658

Опубликована: Окт. 1, 2021

Many physiologic effects of l-glutamate, the major excitatory neurotransmitter in mammalian central nervous system, are mediated via signaling by ionotropic glutamate receptors (iGluRs). These ligand-gated ion channels critical to brain function and centrally implicated numerous psychiatric neurologic disorders. There different classes iGluRs with a variety receptor subtypes each class that play distinct roles neuronal functions. The diversity iGluR subtypes, their unique functional properties roles, has motivated large number studies. Our understanding advanced considerably since first subunit gene was cloned 1989, research focus expanded encompass facets biology have been recently discovered exploit experimental paradigms made possible technological advances. Here, we review insights from more than 3 decades studies an emphasis on progress occurred past decade. We cover structure, function, pharmacology, neurophysiology, therapeutic implications for all assembled subunits encoded 18 genes. SIGNIFICANCE STATEMENT: Glutamate important virtually aspects either involved mediating some clinical features neurological disease or represent target treatment. Therefore, pharmacology this will advance our many at molecular, cellular, system levels provide new opportunities treat patients.

Язык: Английский

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CaMKII: a central molecular organizer of synaptic plasticity, learning and memory

Nature reviews. Neuroscience, Год журнала: 2022, Номер 23(11), С. 666 - 682

Опубликована: Сен. 2, 2022

Язык: Английский

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Linking glutamate receptor movements and synapse function

Science, Год журнала: 2020, Номер 368(6496)

Опубликована: Июнь 11, 2020

Receptors moving in and out of the synapse The number neurotransmitter receptors their spatial organization on postsynaptic site is a central determinant synaptic efficacy. Sophisticated techniques to visualize track movement single molecules have provided us with profound new insights into these dynamics. We now know that undergo movements different scales. Groc Choquet review our present understanding mechanisms regulate glutamate receptor localization clustering. Receptor are fundamental basic function participate many forms plasticity. Science , this issue p. eaay4631

Язык: Английский

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Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk

Genes & Diseases, Год журнала: 2023, Номер 11(1), С. 103 - 134

Опубликована: Март 24, 2023

Wnt signaling plays a major role in regulating cell proliferation and differentiation. The ligands are family of 19 secreted glycoproteins that mediate their effects via binding to Frizzled receptors LRP5/6 coreceptors transducing the signal either through β-catenin canonical pathway or series other proteins noncanonical pathway. Many individual components both have additional functions throughout body, establishing complex interplay between pathways. This crosstalk pathways gives vital many cellular organ processes. Dysregulation this system has been implicated diseases affecting wide array systems, including cancer embryological defects, can even cause embryonic lethality. complexity its interacting made target for therapeutic treatments. However, stimulatory inhibitory treatments come with potential risks need be addressed. review synthesized much current knowledge on pathway, beginning history signaling. It thoroughly described different variants signaling, canonical, Wnt/PCP, Wnt/Ca2+ Further description involved each involvement Finally, explained various processes

Язык: Английский

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NMDA receptor functions in health and disease: Old actor, new dimensions

Neuron, Год журнала: 2023, Номер 111(15), С. 2312 - 2328

Опубликована: Май 25, 2023

Язык: Английский

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LTP induction by structural rather than enzymatic functions of CaMKII

Nature, Год журнала: 2023, Номер 621(7977), С. 146 - 153

Опубликована: Авг. 30, 2023

Learning and memory are thought to require hippocampal long-term potentiation (LTP), one of the few central dogmas molecular neuroscience that has stood undisputed for more than three decades is LTP induction requires enzymatic activity Ca

Язык: Английский

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Synaptic memory and CaMKII

Physiological Reviews, Год журнала: 2023, Номер 103(4), С. 2897 - 2945

Опубликована: Июнь 8, 2023

Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and long-term potentiation (LTP) were discovered within a decade of each other have been inextricably intertwined ever since. However, like many marriages, it has had its up downs. Based on the unique biochemical properties CaMKII, was proposed as memory molecule before any physiological linkage made to LTP. reviewed here, convincing CaMKII synaptic physiology behavior took decades. New technologies critical in this journey, including vitro brain slices, mouse genetics, single-cell molecular pharmacological reagents, structure, two-photon microscopy, new investigators attracted by exciting challenge. This review tracks journey assesses state marriage 40 years on. The collective literature impels us propose relatively simple model for involving following steps that drive process: 1) entry through N-methyl-d-aspartate (NMDA) receptors activates CaMKII. 2) undergoes autophosphorylation resulting constitutive, -independent activity exposure binding site NMDA receptor subunit GluN2B. 3) Active translocates postsynaptic density (PSD) binds cytoplasmic C-tail 4) CaMKII-GluN2B complex initiates structural rearrangement PSD may involve liquid-liquid phase separation. 5) involves PSD-95 scaffolding protein, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPARs), their transmembrane AMPAR-regulatory (TARP) auxiliary subunits, an accumulation AMPARs underlies potentiation. 6) stability modified is maintained complex. 7) By process exchange or interholoenzyme phosphorylation maintains face turnover. There are important proteins participate enlargement spine modulation maintain In we critically discuss data underlying steps. As will become clear, some these more firmly grounded than others, provide suggestions how evidence supporting can be strengthened or, based data, replaced. Although long one, prospect having detailed cellular understanding learning at hand.

Язык: Английский

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Regulation of NMDA glutamate receptor functions by the GluN2 subunits

Journal of Neurochemistry, Год журнала: 2020, Номер 154(2), С. 121 - 143

Опубликована: Янв. 24, 2020

Abstract The N ‐methyl‐ D ‐aspartate receptors (NMDARs) are ionotropic glutamate that mediate the flux of calcium (Ca 2+ ) into post‐synaptic compartment. Ca influx subsequently triggers activation various intracellular signalling cascades underpin multiple forms synaptic plasticity. Functional NMDARs assembled as heterotetramers composed two obligatory GluN1 subunits and GluN2 or GluN3 subunits. Four different (GluN2A‐D) present throughout central nervous system; however, they differentially expressed, both developmentally spatially, in a cell‐ synapse‐specific manner. Each subunit confers with distinct ion channel properties trafficking pathways. Regulated membrane is dynamic process ultimately determines number at synapses, controlled by subunit‐specific interactions regulatory proteins. Here we review recent progress made towards understanding molecular mechanisms regulate GluN2‐containing NMDARs, focusing on roles several key proteins interact via their carboxyl termini. image

Язык: Английский

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Sustained effects of rapidly acting antidepressants require BDNF-dependent MeCP2 phosphorylation

Nature Neuroscience, Год журнала: 2021, Номер 24(8), С. 1100 - 1109

Опубликована: Июнь 28, 2021

Язык: Английский

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RNA-binding proteins balance brain function in health and disease

Physiological Reviews, Год журнала: 2020, Номер 101(3), С. 1309 - 1370

Опубликована: Окт. 1, 2020

Posttranscriptional gene expression including splicing, RNA transport, translation, and decay provides an important regulatory layer in many if not all molecular pathways. Research the last decades has positioned RNA-binding proteins (RBPs) right center of posttranscriptional regulation. Here, we propose interdependent networks RBPs to regulate complex pathways within central nervous system (CNS). These are involved multiple aspects neuronal development functioning, higher cognition. Therefore, it is sufficient unravel individual contribution a single RBP its consequences but rather study understand tight interplay between different RBPs. In this review, summarize recent findings field biology discuss Second, emphasize underlying dynamics network how might key processes such as neurogenesis, synaptic transmission, plasticity. Importantly, envision that dysfunction specific could lead perturbation network. This would have direct indirect (compensatory) effects mRNA binding translational control leading global changes cellular programs general plasticity particular. focus on cause neuropsychiatric neurodegenerative disorders. Based findings, alterations entire account for phenotypic dysfunctions observed diseases neurodegeneration, epilepsy, autism spectrum

Язык: Английский

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