OptoGluNAM4.1, a Photoswitchable Allosteric Antagonist for Real-Time Control of mGlu 4 Receptor Activity

Rovira, Xavier; Trapero, Ana; Pittolo, Silvia; Zussy, Charleine; Faucherre, Adèle; Jopling, Chris; Giraldo, Jesús; Pin, Jean‐Philippe; Gorostiza, Pau; Goudet, Cyril; Llebaría, Amadeu

doi:10.1016/j.chembiol.2016.06.013

Cited by 74 publications

(74 citation statements)

References 19 publications

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“…More recently, this approach has refined through the use of non-tethered photoswitchable allosteric ligands that possess the properties of an allosteric modulator, but adopt inactive conformations when exposed to light. Discovery of photoswitchable allosteric modulators for the mGlu 5 (Pittolo et al, 2014) and mGlu 4 receptors (Rovira et al, 2016) allows fast and direct modulation of endogenous receptor subtypes in a particular brain region. Collectively, these tools have the promise to provide unprecedented insights into the biology and circuitry underlying numerous CNS diseases.…”

Section: Discussionmentioning

confidence: 99%

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

Foster

Conn

2017

Neuron

210

171

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G-protein coupled receptors (GPCRs) play critical roles in regulating brain function. Recent advances have greatly expanded our understanding of these receptors as complex signaling machines that can adopt numerous conformations and modulate multiple downstream signaling pathways. While agonists and antagonists have traditionally been pursued to target GPCRs, allosteric modulators provide several mechanistic advantages including the ability to distinguish between closely related receptor subtypes. Recently, the discovery of allosteric ligands that confer bias and modulate some, but not all, of a given receptor's downstream signaling pathways can provide pharmacological modulation of brain circuitry with remarkable precision. In addition, allosteric modulators with unprecedented specificity have been developed that can differentiate between subpopulations of a given receptor subtype based on the receptor's dimerization state. These advances are not only providing insight into the biological roles of specific receptor populations, but hold great promise for treating numerous CNS disorders.

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Section: Discussionmentioning

confidence: 99%

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

Foster

Conn

2017

Neuron

210

171

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“…A photoswitchable small molecule mu opioid agonist fentanyl has also been developed as well using this approach [69]. Diffusible photoswitches have also been developed to allosterically modulate metabotrophic glutamate receptors [70,71**]. Additional, neuropeptide photo-ligand mimics are in development and offer exciting extensions of this early work.…”

Section: Photopharmacologymentioning

confidence: 99%

Optogenetic approaches for dissecting neuromodulation and GPCR signaling in neural circuits

Spangler

Bruchas

2017

Current Opinion in Pharmacology

100

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Optogenetics has revolutionized neuroscience by providing means to control cell signaling with spatiotemporal control in discrete cell types. In this review, we summarize four major classes of optical tools to manipulate neuromodulatory GPCR signaling: opsins (including engineered chimeric receptors); photoactivatable proteins; photopharmacology through caging - photoswitchable molecules; fluorescent protein based reporters and biosensors. Additionally, we highlight technologies to utilize these tools in vitro and in vivo, including Cre dependent viral vector expression and two-photon microscopy. These emerging techniques targeting specific members of the GPCR signaling pathway offer an expansive base for investigating GPCR signaling in behavior and disease states, in addition to paving a path to potential therapeutic developments.

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“…Multiple light‐gated metabotropic glutamate receptors (LimGluRs) have been engineered . Levitz et al show that photocontrol over their LimGluR version requires 4'D stereochemistry of MAG, as opposed to 4'L (as for LiGluR and LiGluN).…”

Section: Glutamate Receptorsmentioning

confidence: 99%

Synapses in the spotlight with synthetic optogenetics

Berlin

Isacoff

2017

EMBO Reports

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Membrane receptors and ion channels respond to various stimuli and relay that information across the plasma membrane by triggering specific and timed processes. These include activation of second messengers, allowing ion permeation, and changing cellular excitability, to name a few. Gaining control over equivalent processes is essential to understand neuronal physiology and pathophysiology. Recently, new optical techniques have emerged proffering new remote means to control various functions of defined neuronal populations by light, dubbed optogenetics. Still, optogenetic tools do not typically address the activity of receptors and channels native to neurons (or of neuronal origin), nor gain access to their signaling mechanisms. A related method-synthetic optogenetics-bridges this gap by endowing light sensitivity to endogenous neuronal receptors and channels by the appending of synthetic, light-receptive molecules, or photoswitches. This provides the means to photoregulate neuronal receptors and channels and tap into their native signaling mechanisms in select regions of the neurons, such as the synapse. This review discusses the development of synthetic optogenetics as a means to study neuronal receptors and channels remotely, in their natural environment, with unprecedented spatial and temporal precision, and provides an overview of tool design, mode of action, potential clinical applications and insights and achievements gained.

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OptoGluNAM4.1, a Photoswitchable Allosteric Antagonist for Real-Time Control of mGlu 4 Receptor Activity

Cited by 74 publications

References 19 publications

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

Optogenetic approaches for dissecting neuromodulation and GPCR signaling in neural circuits

Synapses in the spotlight with synthetic optogenetics

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