Mechanisms of differential desensitization of metabotropic glutamate receptors

Cell Reports, Journal Year: 2021, Volume and Issue: 35(4), P. 109050 - 109050

Published: April 1, 2021

G protein-coupled receptors (GPCRs) interact with intracellular transducers to control both signal initiation and desensitization, but the distinct mechanisms that regulation of different GPCR subtypes are unclear. Here we use fluorescence imaging electrophysiology examine metabotropic glutamate receptor (mGluR) family. We find properties across in rapid desensitization internalization, striking differences between group II mGluRs. mGluR3, not mGluR2, undergoes glutamate-dependent trafficking, recycling. map mGluRs variable Ser/Thr-rich sequences C-terminal domain (CTD) interaction kinases β-arrestins. Finally, identify a cancer-associated mutation, G848E, within mGluR3 CTD enhances β-arrestin coupling enabling an analysis β-arrestin-coupling revealing biased variants. Together, this work provides framework for understanding functional roles mGluR subtypes.

Language: Английский

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Aberrant activity of mitochondrial NCLX is linked to impaired synaptic transmission and is associated with mental retardation

Communications Biology, Journal Year: 2021, Volume and Issue: 4(1)

Published: June 2, 2021

Calcium dynamics control synaptic transmission. triggers vesicle fusion, determines release probability, modulates recycling, participates in long-term plasticity and regulates cellular metabolism. Mitochondria, the main source of energy, serve as calcium signaling hubs. Mitochondrial transients are primarily determined by balance between influx, mediated mitochondrial uniporter (MCU), efflux through sodium/lithium/calcium exchanger (NCLX). We identified a human recessive missense SLC8B1 variant that impairs NCLX activity is associated with severe mental retardation. On this basis, we examined effect deleting mice on homeostasis, activity, plasticity. Neuronal mitochondria exhibited basal overload, membrane depolarization, reduction amplitude rate influx efflux. observed smaller cytoplasmic presynaptic terminals NCLX-KO neurons, leading to lower probability weaker In agreement, facilitation hippocampal slices was enhanced. Importantly, deletion abolished long term potentiation Schaffer collateral synapses. Our results show controls crucial for defining strength well short- plasticity, key elements learning memory processes.

Language: Английский

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Cell specific photoswitchable agonist for reversible control of endogenous dopamine receptors

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Aug. 6, 2021

Abstract Dopamine controls diverse behaviors and their dysregulation contributes to many disorders. Our ability understand manipulate the function of dopamine is limited by heterogenous nature dopaminergic projections, diversity neurons that are regulated dopamine, varying distribution five receptors (DARs), complex dynamics release. In order improve our specifically modulate distinct DARs, here we develop a photo-pharmacological strategy using Membrane anchored Photoswitchable orthogonal remotely tethered agonist for receptor (MP-D). design selectively targets D1R/D5R subtypes, most potently D1R (MP-D1 ago ), as shown in HEK293T cells. vivo, targeted dorsal striatal medium spiny where photo-activation MP-D1 increased movement initiation, although further work required assess effects on neuronal function. method combines ligand cell type-specificity with temporally precise reversible activation control specific aspects movement. results provide template analyzing receptors.

Language: Английский

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Optical control of Class A G protein-coupled receptors with photoswitchable ligands

Current Opinion in Pharmacology, Journal Year: 2022, Volume and Issue: 63, P. 102192 - 102192

Published: March 4, 2022

The field of photopharmacology Class A GPCR ligands has recently attracted attention. In this review we analyze 31 papers on currently available photoswitchable for GPCRs. Using the six most recurring terms all combined paper abstracts, one can extract overarching goal area research: "Photoswitchable control receptor activity with light" (represented in TOC graphic). We design, photochemistry and pharmacology ligands. Trends, challenges limitations will be discussed. number efficient that allow optical modulation function various vitro assays are presented. Moreover, vivo is within reach first reports to end highlighted.

Language: Английский

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A guide to designing photocontrol in proteins: methods, strategies and applications

Biological Chemistry, Journal Year: 2022, Volume and Issue: 403(5-6), P. 573 - 613

Published: March 31, 2022

Light is essential for various biochemical processes in all domains of life. In its presence certain proteins inside a cell are excited, which either stimulates or inhibits subsequent cellular processes. The artificial photocontrol specifically growing interest the investigation scientific questions on organismal, and molecular level as well development medicinal drugs biocatalytic tools. For targeted design proteins, three major methods have been developed over last decades, employ chemical engineering small-molecule photosensitive effectors (photopharmacology), incorporation photoactive non-canonical amino acids by genetic code expansion (photoxenoprotein engineering), fusion with photoreactive biological modules (hybrid protein optogenetics). This review compares different their strategies current applications light-regulation provides background information useful implementation each technique.

Language: Английский

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A general method for near-infrared photoswitching in biology, demonstrated by the >700 nm photocontrol of GPCR activity in brain slices

Published: April 30, 2024

Azobenzene molecular switches are widely used to photocontrol material properties, and biological activity in cell culture, via photoisomerisation between E Z isomers. However, because population photoswitching is incomplete, their dynamic range of property control often small; they cannot be operated with red/NIR light, usually not applicable deep tissue. Here, we demonstrate a general method for efficient single-photon azobenzenes, glutamate receptor activity, at >700 nm live We use chromophore auxiliaries perform intramolecular energy transfer bioactive which drives fast bulk Z→E isomerisation up even >97% completeness. The auxiliary/azobenzene dyads allow photon-efficiency that can higher than direct azobenzene E→Z the UV region; biocompatible photostable. Crucially, performance properties intrinsic, i.e. auxiliary-based switching will identically any dilution affected by biodistribution. show these created straightforwardly from most systems, auxiliary chromophores, without tricky redesign or re-optimisation. After outlining some rules photoswitching, guide its broader adoption, conclude using make first demonstration NIR chemical over culture intact brain

Language: Английский

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DART.2: bidirectional synaptic pharmacology with thousandfold cellular specificity

Nature Methods, Journal Year: 2024, Volume and Issue: 21(7), P. 1288 - 1297

Published: June 14, 2024

Language: Английский

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Visible‐ and Near‐Infrared Light‐Driven Molecular Photoswitches for Biological Applications

Advanced Functional Materials, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 19, 2024

Abstract Molecular photoswitches can undergo isomerization under light exposure, making them uniquely attractive for high spatiotemporal resolution remote control of biological functions. Visible and near‐infrared (NIR) light, with their low energy consumption, safety, strong tissue penetration, are particularly suitable applications. Therefore, developing visible‐ NIR light‐driven molecular use is great significance. This review introduces the most common presents state‐of‐art applications in bioimaging, biosensing, drug delivery, photocontrolled cancer phototherapy, photopharmacology. The opportunities challenges future development outlined.

Language: Английский

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Interrogating surface versus intracellular transmembrane receptor populations using cell-impermeable SNAP-tag substrates

Chemical Science, Journal Year: 2020, Volume and Issue: 11(30), P. 7871 - 7883

Published: Jan. 1, 2020

Impermeable SNAP-tag substrates allow exclusive labelling of receptors on the cell membrane for nanoscopy, SiMPull and in vivo use.

Language: Английский

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In Vivo Photopharmacology Enabled by Multifunctional Fibers

ACS Chemical Neuroscience, Journal Year: 2020, Volume and Issue: 11(22), P. 3802 - 3813

Published: Oct. 27, 2020

Photoswitchable ligands can add an optical switch to a target receptor or signaling cascade and enable reversible control of neural circuits. The application this approach, termed photopharmacology, behavioral experiments has been impeded by lack integrated hardware capable delivering both light compounds deep brain regions in moving subjects. Here, we devise hybrid photochemical genetic approach neurons using photoswitchable agonist the capsaicin TRPV1, red-AzCA-4. Using multifunctional fibers with microfluidic capabilities, delivered transgene coding for TRPV1 into ventral tegmental area (VTA). This sensitized excitatory VTA red-AzCA-4, allowing us optically conditioned place preference mice, thus extending applications photopharmacology experiments. Applied endogenous receptors, our may accelerate future studies molecular mechanisms underlying animal behavior.

Language: Английский

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