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

Projection-Targeted Photopharmacology Reveals Distinct Anxiolytic Roles for Presynaptic mGluR2 in Prefrontal- and Insula-Amygdala Synapses DOI Creative Commons
Hermany Munguba, Vanessa A. Gutzeit,

Ipsit Srivastava

et al.

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

Published: Jan. 16, 2024

Dissecting how membrane receptors regulate neural circuit function is critical for deciphering basic principles of neuromodulation and mechanisms therapeutic drug action. Classical pharmacological genetic approaches are not well-equipped to untangle the roles specific receptor populations, especially in long-range projections which coordinate communication between brain regions. Here we use viral tracing, electrophysiological, optogenetic, photopharmacological determine presynaptic metabotropic glutamate 2 (mGluR2) activation basolateral amygdala (BLA) alters anxiety-related behavior. We find that mGluR2-expressing neurons from ventromedial prefrontal cortex (vmPFC) posterior insular (pIC) preferentially target distinct cell types subregions BLA different forms avoidant Using projection-specific activation, mGluR2-mediated inhibition vmPFC-BLA, but pIC-BLA, connections can produce long-lasting decreases spatial avoidance. In contrast, pIC-BLA decreased social avoidance, novelty-induced hypophagia, increased exploratory behavior without impairing working memory, establishing this projection as a novel treatment anxiety disorders. Overall, work reveals new aspects with implications while powerful approach optical mapping action via photopharmacology.

Language: Английский

Citations

1
Light-Activatable, Cell-Type Specific Labeling of the Nascent Proteome DOI Creative Commons

H. T. Evans,

Tongil Ko, Manuela Oliveira

et al.

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(19), P. 3473 - 3481

Published: Sept. 23, 2024

Elucidating the mechanisms by which protein synthesis contributes to complex biological processes has remained a challenging endeavor. This is particularly true in field of neuroscience, where multiple, tightly regulated periods new different cell-types are thought facilitate intricate neurological functions, such as memory formation. Current methods for labeling

Language: Английский

Citations

1
Orthogonal Control of Neuronal Circuits and Behavior Using Photopharmacology DOI
Rossella Castagna, Dušan Kolarski, Romain Durand-de Cuttoli

et al.

Journal of Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 72(7), P. 1433 - 1442

Published: June 23, 2022

Language: Английский

Citations

7
Thousandfold Cell-Specific Pharmacology of Neurotransmission DOI Open Access
Brenda C. Shields, Hai Yan, Shaun S.X. Lim

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Oct. 21, 2022

SUMMARY Cell-specific pharmaceutical technologies promise mechanistic insight into clinical drugs―those that treat, and often define, human disease. In particular, DART (drug acutely restricted by tethering) achieves genetically programmable control of drug concentration over cellular dimensions. The method is compatible with pharmaceuticals amenable to studies in behaving animals. Here, we describe DART.2 , comprising three advances. First, improve the efficiency chemical capture, enabling cell-specific accumulation ∼3,000-times ambient 15 min. Second, develop tracer reagents, providing a behavior-independent measure target engagement each animal. Third, extend positive allosteric modulators outline design principles for this clinically significant class. We showcase platform four pharmaceuticals―two weaken excitatory (AMPAR) or inhibitory (GABA A R) neurotransmission, two strengthen these forms synaptic communication. Across labs, tested reagents mouse cerebellum, basal ganglia, visual cortex, retina. Collectively, demonstrate robust, bidirectional editing neurotransmission. provide distribution validated community principles, synthetic building blocks application diverse pharmaceuticals.

Language: Английский

Citations

6
Deuteration provides a general strategy to enhance azobenzene-based photopharmacology DOI Creative Commons
Kilian Roßmann, Alberto J. Gonzalez-Hernandez, Rahul Bhuyan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 9, 2023

ABSTRACT Herein, we present deuterated azobenzene photoswitches as a general means of enhancing photopharmacological molecules. Deuteration can improve performance in terms light sensitivity, photoswitch efficiency, and kinetics with minimal alteration to the underlying structure ligand. We report synthesized azobenzene-based ligands for optimized optical control ion channel G protein-coupled receptor function live cells, setting stage straightforward, widespread adoption this approach.

Language: Английский

Citations

2
Fluorescence of the Retinal Chromophore in Microbial and Animal Rhodopsins DOI Open Access
Dmitrii M. Nikolaev, Andrey A. Shtyrov,

Sergey Yu. Vyazmin

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(24), P. 17269 - 17269

Published: Dec. 8, 2023

Fluorescence of the vast majority natural opsin-based photoactive proteins is extremely low, in accordance with their functions that depend on efficient transduction absorbed light energy. However, several recently proposed classes engineered rhodopsins enhanced fluorescence, along discovery a new highly fluorescent rhodopsin, NeoR, opened way to exploit these transmembrane as sensors and draw more attention studies this untypical rhodopsin property. Here, we review available data fluorescence retinal chromophore microbial animal photocycle intermediates, well different isomers protonated Schiff base various solvents gas phase.

Language: Английский

Citations

2
Deuteration as a General Strategy to Enhance Azobenzene‐Based Photopharmacology DOI Creative Commons
Kilian Roßmann, Alberto J. Gonzalez-Hernandez, Rahul Bhuyan

et al.

Angewandte Chemie, Journal Year: 2024, Volume and Issue: 136(39)

Published: June 20, 2024

Abstract 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

0
Fluorescence of the retinal chromophore in microbial and animal rhodopsins DOI Creative Commons
Dmitrii M. Nikolaev, Andrey A. Shtyrov,

Sergey Yu. Vyazmin

et al.

Published: Nov. 14, 2023

Fluorescence of the vast majority natural opsin-based photoactive proteins is extremely low in accordance with their functions that depend on efficient transduction absorbed light energy. However, recently proposed several classes engineered rhodopsins enhanced fluorescence along discovery a new highly fluorescent rhodopsin, NeoR, opened way to exploit these transmembrane as sensors and draw more attention studies this untypical property. Here we review available data retinal chromophore microbial animal photocycle intermediates well different isomers protonated Schiff base solvents gas phase.

Language: Английский

Citations

1
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

Citations

0