Optical profiling of NMDA receptor molecular diversity at synaptic and extrasynaptic sites DOI Creative Commons

Antoine Sicard,

Meilin Tian,

Zakaria Mostefai

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 16, 2024

Abstract Neurotransmitter receptors are the linchpin of neuronal communication. These often form large multimeric complexes that differ in their subunit composition, distribution and signaling properties. Studying neurotransmitter native tissues with stoichiometry resolution remains challenging. This is case NMDA (NMDARs), a class glutamate-gated ion channels playing essential roles brain development plasticity. co-exist as multiple subtypes, GluN1/GluN2A (GluN2A diheteromers), GluN1/GluN2B (GluN2B diheteromers) GluN1/2A/2B (GluN2A/2B triheteromers) prevailing. Here, we designed photochemical tool (Opto2B) enabling specific reversible modulation GluN2B diheteromers (while leaving other receptor subtypes unaffected). Using Opto2B, established differential contribution to synaptic extrasynaptic NMDAR pools, clarifying decades controversial research. In particular, show adult CA1 pyramidal cells, GluN2A-receptors predominate both no preferential currents. Our study paves way for interrogating diversity unprecedented molecular spatio-temporal resolution.

Language: Английский

Emerging modes of regulation of neuromodulatory G protein-coupled receptors DOI
Alberto J. Gonzalez-Hernandez, Hermany Munguba, Joshua Levitz

et al.

Trends in Neurosciences, Journal Year: 2024, Volume and Issue: 47(8), P. 635 - 650

Published: June 12, 2024

Language: Английский

Citations

6
A general method for near-infrared photoswitching in biology, demonstrated by the >700 nm photocontrol of GPCR activity in brain slices DOI Creative Commons

Benedikt Baumgartner,

Viktorija Glembockyte, Alberto J. Gonzalez-Hernandez

et al.

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

Citations

5
DART.2: bidirectional synaptic pharmacology with thousandfold cellular specificity DOI
Brenda C. Shields, Hai Yan, Shaun S.X. Lim

et al.

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

Published: June 14, 2024

Language: Английский

Citations

5
Projection-targeted photopharmacology reveals distinct anxiolytic roles for presynaptic mGluR2 in prefrontal- and insula-amygdala synapses DOI
Hermany Munguba,

Ipsit Srivastava,

Vanessa A. Gutzeit

et al.

Neuron, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Light‐Activated Pharmacological Tools for Exploring the Cholinergic System DOI Creative Commons

Alessio Colleoni,

Giulia Galli, Clelia Dallanoce

et al.

Medicinal Research Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: March 23, 2025

ABSTRACT Cholinergic transmission plays a critical role in both the central and peripheral nervous systems, affecting processes such as learning, memory, inflammation. Conventional cholinergic drugs generally suffer from poor selectivity temporal precision, leading to undesired effects limited therapeutic efficacy. Photopharmacology aims overcome limitations of traditional using photocleavable or photoswitchable ligands spatiotemporal patterns illumination. Spanning muscarinic nicotinic modulators cholinesterase inhibitors, this review explores development application light‐activated compounds tools for unraveling signaling physiological pathological contexts, while also paving way innovative phototherapeutic approaches.

Language: Английский

Citations

0
A new approach to psoriasis therapy: photoswitchable A3 adenosine receptor activation DOI
Federica Cherchi, Elisabetta Coppi

Purinergic Signalling, Journal Year: 2025, Volume and Issue: unknown

Published: April 7, 2025

Language: Английский

Citations

0
Optical Approaches for Investigating Neuromodulation and G Protein–Coupled Receptor Signaling DOI Creative Commons
David J. Marcus, Michael R. Bruchas

Pharmacological Reviews, Journal Year: 2023, Volume and Issue: 75(6), P. 1119 - 1139

Published: Oct. 17, 2023

Despite the fact that roughly 40% of all US Food and Drug Administration (FDA)-approved pharmacological therapeutics target G protein–coupled receptors (GPCRs), there remains a gap in our understanding physiologic functional role these at systems level. Although heterologous expression vitro assays have revealed tremendous amount about GPCR signaling cascades, how cascades interact across cell types, tissues, organ obscure. Classic behavioral pharmacology experiments lack both temporal spatial resolution to resolve long-standing issues. Over past half century, has been concerted effort toward development optical tools for signaling. From initial ligand uncaging approaches more recent optogenetic techniques, strategies allowed researchers probe longstanding questions vivo vitro. These employed biologic interrogation everything from specific intramolecular events level spatiotemporally manner. In this review, we present historical perspective on motivation behind variety toolkits generated Here highlight used uncover distinct populations GPCRs their

Significance Statement

(GPCRs) remain one most targeted classes proteins pharmaceutical intervention, yet still limited unique effect physiology behavior discuss vast array techniques devised vivo.

Language: Английский

Citations

7
Deuteration as a General Strategy to Enhance Azobenzene‐Based Photopharmacology DOI
Kilian Roßmann, Alberto J. Gonzalez-Hernandez, Rahul Bhuyan

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: unknown

Published: June 20, 2024

Chemical photoswitches have become a widely used approach for the remote control of biological functions with spatiotemporal precision. Several molecular scaffolds been implemented to improve photoswitch characteristics, ranging from nature itself (e.g. azobenzenes, dithienylethenes, hemithioindigo) fine-tuning aromatic units and substituents. Herein, we present deuterated azobenzene as general means enhancing performance photopharmacological molecules. Deuteration can in terms light sensitivity (higher molar extinction coefficient), efficiency photoisomerization quantum yield), kinetics (faster macroscopic rate photoisomerization) minimal alteration underlying structure ligand. We report synthesized azobenzene-based ligands optimized optical ion channel G protein-coupled receptor (GPCR) function live cells, setting stage straightforward, widespread adoption this approach.

Language: Английский

Citations

2
Azobenzenes can achieve near-infrared photocontrol in biological systems, with quantitative Z→E photoisomerization, via singlet manifold photoredox DOI Creative Commons

Benedikt Baumgartner,

Viktorija Glembockyte, Robert J. Mayer

et al.

Published: Sept. 14, 2023

Here we develop a high-performance approach to photoswitching, by exploiting singlet manifold photoredox between azobenzenes and covalently attached auxiliary chromophores. This enables well-penetrating red/NIR light of 630-740 nm, which usually do not respond, perform Z→E photoisomerisation that is also 100% complete highly photon-efficient. Crucially, this process biocompatible, tolerates molecular oxygen, photostable, it avoids the drawbacks triplet photochemistry; substituent patterns need re-engineering harness it. We provide library redox potentials predict performance, show its tolerance linker length, E→Z-promoting tetra-ortho-substitutions can be combined with give fast efficient bidirectional Z⇄E photoswitches for visible/NIR. then demonstrate first use single photon NIR reversible photopharmaceutical control in live cells under physiological conditions, modulating G protein-coupled receptor activity. These stringent assays switching robust method photocontrol should find applications materials, biophysics, "chemical optogenetics v2.0" living systems.

Language: Английский

Citations

6
Optical Control of Dopamine D2-like Receptors with Cell-Specific Fast-Relaxing Photoswitches DOI Creative Commons
Belinda E. Hetzler,

Prashant Donthamsetti,

Zisis Peitsinis

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(34), P. 18778 - 18788

Published: Aug. 16, 2023

Dopamine D2-like receptors (D2R, D3R, and D4R) control diverse physiological behavioral functions are important targets for the treatment of a variety neuropsychiatric disorders. Their complex distribution activation kinetics in brain make it difficult to target specific receptor populations with sufficient precision. We describe new toolkit light-activatable, fast-relaxing, covalently taggable chemical photoswitches that fully activate, partially or block receptors. This technology combines spatiotemporal precision photoswitchable ligand (P) cell type spatial specificity genetically encoded membrane anchoring protein (M) which P tethers. These tools set stage targeting endogenous signaling molecular, cellular, using only one wavelength light.

Language: Английский

Citations

4