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Optical control of neuronal ion channels and receptors

Abstract

Light-controllable tools provide powerful means to manipulate and interrogate brain function with relatively low invasiveness and high spatiotemporal precision. Although optogenetic approaches permit neuronal excitation or inhibition at the network level, other technologies, such as optopharmacology (also known as photopharmacology) have emerged that provide molecular-level control by endowing light sensitivity to endogenous biomolecules. In this Review, we discuss the challenges and opportunities of photocontrolling native neuronal signalling pathways, focusing on ion channels and neurotransmitter receptors. We describe existing strategies for rendering receptors and channels light sensitive and provide an overview of the neuroscientific insights gained from such approaches. At the crossroads of chemistry, protein engineering and neuroscience, optopharmacology offers great potential for understanding the molecular basis of brain function and behaviour, with promises for future therapeutics.

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Fig. 1: Main strategies to endow light sensitivity to neuronal receptors and ion channels.
Fig. 2: Photocontrol of ion channel and receptor biophysics and pharmacology.
Fig. 3: Optopharmacology for subcellular neuronal studies.
Fig. 4: Optopharmacology for cell-specific and receptor-specific interrogation of synaptic physiology.
Fig. 5: Optopharmacology for behavioural studies.

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Acknowledgements

This work was supported by the French government (‘Investissements d’Avenir’ ANR-10-LABX-54 MEMOLIFE, ANR-11-IDEX-0001-02 PSL University and ANR-11-LABX-0011-01 to P.P.; ANR-JCJC 2014 to A.M.), the European Research Council (ERC Advanced Grant #693021 to P.P.), the Brain and Behavior Research Foundation (NARSAD Young Investigator Award to A.M.) and the US National Institutes of Health (grants #GM053395 and #NS069720 to G.C.R.E.-D.). A.M. was the recipient of a fundamental research prize from the Medisite Foundation for Neuroscience.

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All authors researched data for article, made substantial contributions to the discussion of content, wrote the article and reviewed or edited the manuscript before submission.

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Correspondence to Pierre Paoletti, Graham C. R. Ellis-Davies or Alexandre Mourot.

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Glossary

Chromophores

Molecular groups that are responsible for light absorbance (and thus the colour of the molecule).

Photo-isomerizing group

A molecular group that can be switched between two distinct cis and trans configurations, or isomers, with particular wavelengths of light.

Allosteric modulators

Modulators of the activity of enzymes and receptors that target a ligand-binding site distinct from that to which the substrate or agonist binds.

Quantum yield

The efficiency of a photochemical reaction with respect to the amount of light absorbed.

Bistability

In azobenzenes, the ability for the cis and trans isomers each to be stable under particular illumination conditions and over long periods of time (minutes to days).

Photostationary state

The steady state reached by a photochemical reaction under a given illumination condition. In photo-isomerization, the photostationary state is usually given as a ratio of cis to trans photo-isomers.

Azologization

The process by which an established pharmacological compound is converted into a photoswitchable one, through the introduction of an azobenzene moiety.

Singlet oxygen

A specific state of the diatomic oxygen molecule (O2) that is usually produced by light irradiation and that can cause photo-damage to nearby molecules.

Genetic code expansion

A methodology that allows the introduction of unnatural amino acids into a protein. It is usually based on the re-assignment of an engineered stop codon within the protein coding sequence.

Agonist deactivation kinetics

Current decay following agonist removal from a ligand-gated ion channel.

Directional selectivity

The ability of a neuron to respond differentially to the direction of the stimulus.

Gliotransmission

The transmission of a signalling molecule that is released from glial cells and that acts on nearby cells (such as neurons).

Topographic maps

Spatially organized representations of a sensory surface (for example, the retina or the skin) in the cortex or other brain areas.

ON and OFF responses

Depolarization (ON) or hyperpolarization (OFF) of bipolar cells in the retina in response to light.

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Paoletti, P., Ellis-Davies, G.C.R. & Mourot, A. Optical control of neuronal ion channels and receptors. Nat Rev Neurosci 20, 514–532 (2019). https://doi.org/10.1038/s41583-019-0197-2

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