Seeing and Cleaving: Turn-Off Fluorophore Uncaging and Its Application in Hydrogel Photopatterning and Traceable Neurotransmitter Photocages DOI Creative Commons

Orsolya Pantl,

Balázs Chiovini,

Gergely Szalay

et al.

ACS Applied Materials & Interfaces, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 5, 2024

The advancements in targeted drug release and experimental neuroscience have amplified the scientific interest photolabile protecting groups (PPGs) photouncaging. growing need for detection of uncaging events has led to development reporters with fluorescence turn-on upon uncaging. In contrast, fluorescent tags turn-off properties been drastically underexplored, although there are applications where they would be sought after. this work, a rhodamine-based tag is developed signal following One-photon photolysis experiments reveal ready loss red UV (365 nm) irradiation, while no significant change observed control absence PPG or irradiation around absorption maximum fluorophore (595 nm). two-photon explored hydrogel photolithography experiments. hydrogel-bound enables power-, dwell time-, wavelength-dependent construction intricate patterns gradients. Finally, prominent caged neurotransmitter (MNI-Glu) modified tag, resulting glutamate precursor named as GlutaTrace traceability successfully applied visualization distribution capillary microinjection selective excitation neurons mouse brain model.

Language: Английский

NMDA receptor functions in health and disease: Old actor, new dimensions DOI Creative Commons
Julien P. Dupuis, Olivier Nicole, Laurent Groc

et al.

Neuron, Journal Year: 2023, Volume and Issue: 111(15), P. 2312 - 2328

Published: May 25, 2023

Language: Английский

Citations

66
Tonic NMDA Receptor Currents in the Brain: Regulation and Cognitive Functions DOI
HaYoung Kim, Soo-Young Choi,

Euisun Lee

et al.

Biological Psychiatry, Journal Year: 2024, Volume and Issue: 96(3), P. 164 - 175

Published: March 13, 2024

Language: Английский

Citations

10
Functional crosstalk of the glycine transporter GlyT1 and NMDA receptors DOI Creative Commons
Dolores Piniella, Francisco Zafra

Neuropharmacology, Journal Year: 2023, Volume and Issue: 232, P. 109514 - 109514

Published: March 31, 2023

NMDA-type glutamate receptors (NMDARs) constitute one of the main (Glu) targets in central nervous system and are involved synaptic plasticity, which is molecular substrate learning memory. Hypofunction NMDARs has been associated with schizophrenia, while overstimulation causes neuronal death neurodegenerative diseases or stroke. The function requires coincidental binding Glu along other cellular signals such as depolarization, presence endogenous ligands that modulate their activity by allosterism. Among these allosteric modulators zinc, protons Gly, an obligatory co-agonist. These characteristics differentiate from receptors, structural bases have begun to be established recent years. In this review we focus on crosstalk between glycine (Gly), whose concentration NMDAR microenvironment maintained various Gly transporters remove release it into medium a regulated manner. GlyT1 transporter particularly task, become target great interest for treatment schizophrenia since its inhibition leads increase levels enhances NMDARs. However, only drug completed phase III clinical trials did not yield expected results. Notwithstanding, there additional drugs continue investigated, hoped knowledge gained recently published 3D structure may allow rational design more effective new drugs. This article part Special Issue "The receptor-receptor interaction therapy".

Language: Английский

Citations

20
Excitatory GluN1/GluN3A glycine receptors (eGlyRs) in brain signaling DOI Creative Commons
Simon Bossi, Lara Pizzamiglio, Pierre Paoletti

et al.

Trends in Neurosciences, Journal Year: 2023, Volume and Issue: 46(8), P. 667 - 681

Published: May 28, 2023

Language: Английский

Citations

20
Loss of Grin2a causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneurons DOI Creative Commons
Chad R. Camp, Anna Vlachos, Chiara Klöckner

et al.

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: Sept. 19, 2023

Abstract N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ionotropic glutamate that mediate a calcium-permeable component to fast excitatory neurotransmission. NMDARs heterotetrameric assemblies of two obligate GluN1 subunits ( GRIN1 ) and GluN2 GRIN2A - GRIN2D ). Sequencing data shows 43% (297/679) all currently known NMDAR disease-associated genetic variants within the gene, which encodes GluN2A subunit. Here, we show unlike missense variants, individuals affected with null demonstrate transient period seizure susceptibility begins during infancy diminishes near adolescence. We increased circuit excitability CA1 pyramidal cell output in juvenile mice both Grin2a +/− −/− mice. These alterations somatic spiking not due global upregulation most Grin genes (including Grin2b Deeper evaluation developing led us uncover age- gene dosing-dependent delays electrophysiological maturation programs parvalbumin (PV) interneurons. report +/+ reach PV between neonatal neurodevelopmental timepoints, reaching until preadolescence, adulthood. Overall, these may represent molecular mechanism describing nature patients.

Language: Английский

Citations

19
The role of N-methyl-D-aspartate glutamate receptors in Alzheimer’s disease: From pathophysiology to therapeutic approaches DOI
Wenying Liu, Yan Li, Tan Zhao

et al.

Progress in Neurobiology, Journal Year: 2023, Volume and Issue: 231, P. 102534 - 102534

Published: Sept. 30, 2023

Language: Английский

Citations

18
Structure and function of GluN1-3A NMDA receptor excitatory glycine receptor channel DOI Creative Commons

Kevin Michalski,

Hiro Furukawa

Science Advances, Journal Year: 2024, Volume and Issue: 10(15)

Published: April 10, 2024

-methyl-d-aspartate receptors (NMDARs) and other ionotropic glutamate (iGluRs) mediate most of the excitatory signaling in mammalian brains response to neurotransmitter glutamate. Uniquely, NMDARs composed GluN1 GluN3 are activated exclusively by glycine, conventionally mediating inhibitory when it binds pentameric glycine receptors. The GluN1-3 vital for regulating neuronal excitability, circuit function, specific behaviors, yet our understanding their functional mechanism at molecular level has remained limited. Here, we present cryo-electron microscopy structures GluN1-3A bound an antagonist, CNQX, agonist, glycine. show a 1-3-1-3 subunit heterotetrameric arrangement unprecedented pattern GluN3A orientation shift between glycine-bound CNQX-bound structures. Site-directed disruption unique interface structure mitigated desensitization. Our study provides foundation distinct structural dynamics that linked function NMDARs.

Language: Английский

Citations

8
Metabotropic signaling within somatostatin interneurons controls transient thalamocortical inputs during development DOI Creative Commons
Deepanjali Dwivedi, Dimitri Dumontier, Mia Sherer

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 26, 2024

Abstract During brain development, neural circuits undergo major activity-dependent restructuring. Circuit wiring mainly occurs through synaptic strengthening following the Hebbian “fire together, wire together” precept. However, select connections, essential for circuit are transient. They effectively connected early in but strongly diminish during maturation. The mechanisms by which transient connectivity recedes unknown. To investigate this process, we characterize thalamocortical inputs, depress onto somatostatin inhibitory interneurons employing optogenetics, chemogenetics, transcriptomics and CRISPR-based strategies mice. We demonstrate that contrast to typical mechanisms, is non-canonical involves metabotropic signaling. Specifically, metabotropic-mediated transcription, of guidance molecules particular, supports elimination connectivity. Remarkably, found process impacts development normal exploratory behaviors adult

Language: Английский

Citations

6
Interactions Involving Glycine and Other Amino Acid Neurotransmitters: Focus on Transporter-Mediated Regulation of Release and Glycine–Glutamate Crosstalk DOI Creative Commons
Luca Raiteri

Biomedicines, Journal Year: 2024, Volume and Issue: 12(7), P. 1518 - 1518

Published: July 8, 2024

Glycine plays a pivotal role in the Central Nervous System (CNS), being major inhibitory neurotransmitter as well co-agonist of Glutamate at excitatory NMDA receptors. Interactions involving and other neurotransmitters are subject different studies. Functional interactions among include modulation release through release-regulating receptors but also transporter-mediated mechanisms. Many involve amino acid transmitters Glycine, Glutamate, GABA. Different studies published during last two decades investigated number depth nerve terminal level CNS areas, providing details mechanisms involved suggesting pathophysiological significances. Here, this evidence is reviewed considering additional recent information available literature, with special (but not exclusive) focus on glycinergic neurotransmission Glycine–Glutamate interactions. Some possible pharmacological implications, although partly speculative, discussed. Dysregulations glutamatergic transmission relevant pathologies. Pharmacological interventions targets (including transporters) under study to develop novel therapies against serious pathological states including pain, schizophrenia, epilepsy, neurodegenerative diseases. Although limitations, it hoped possibly contribute better understanding complex between glycine-mediated transmitters, view current interest potential drugs acting “glycinergic” targets.

Language: Английский

Citations

5
Loss of activation by GABA in vertebrate delta ionotropic glutamate receptors DOI Creative Commons

Giulio Rosano,

Allan Barzasi,

Timothy Lynagh

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(6)

Published: Jan. 29, 2024

Ionotropic glutamate receptors (iGluRs) mediate excitatory signals between cells by binding neurotransmitters and conducting cations across the cell membrane. In mammalian brain, most of these are mediated two types iGluRs: AMPA NMDA (i.e. iGluRs sensitive to 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid N-methyl-D-aspartic acid, respectively). Delta-type mammals also form neurotransmitter-binding channels in membrane, but contrast, their channel is not activated neurotransmitter binding, raising biophysical questions about iGluR activation biological role delta iGluRs. We therefore investigated divergence from cousins using molecular phylogenetics, electrophysiology, site-directed mutagenesis. find that found numerous bilaterian animals (e.g., worms, starfish, vertebrates) closely related receptors, both genetically functionally. Surprisingly, we observe many family classical inhibitory neurotransmitter, γ-aminobutyric (GABA). Finally, identify nine amino substitutions likely gave rise inactivity today’s iGluRs, mutations abolish activity when engineered into active invertebrate partly inducing receptor desensitization. These results offer insight point a for GABA signaling invertebrates.

Language: Английский

Citations

4