Reversibly Caged Glutamate:  A Photochromic Agonist of Ionotropic Glutamate Receptors

Volgraf, Matthew; Gorostiza, Pau; Szobota, Stephanie; Helix, Max R; Isacoff, Ehud Y.; Trauner, Dirk

doi:10.1021/ja067269o

Cited by 157 publications

(181 citation statements)

References 20 publications

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“…This compound turned out to be a highly effective photochromic agonist of certain kainate receptors. [73] Its application to GluK1 and GluK2 channels expressed in HEK293 cells demonstrated the reversible control of inward currents in a light-dependent manner. In this case, the trans state of the azobenzene preferentially activates the receptors, and 4-GluAzo showed a slightly higher selectivity for GluK1 than for GluK2.…”

Section: Reviewsmentioning

confidence: 99%

“…When applied to dissociated rat hippocampal neurons, 4-GluAzo functioned as "reversibly caged" glutamate. [73] Action potential firing could be triggered by changing from 380 to 500 nm light and stopped by switching back to the lower wavelength. In subsequent studies, the burst firing of cerebellar Purkinje neurons could be effectively controlled with 4-GluAzo.…”

Section: Reviewsmentioning

confidence: 99%

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Optochemical Genetics

Fehrentz¹,

Schönberger²,

Trauner³

2011

Angew Chem Int Ed

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347

261

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Transmembrane receptors allow a cell to communicate with its environment in response to a variety of input signals. These can be changes in the concentration of ligands (e.g. hormones or neurotransmitters), temperature, pressure (e.g. acoustic waves or touch), transmembrane potential, or light intensity. Many important receptors have now been characterized in atomic detail and our understanding of their functional properties has markedly increased in recent years. As a consequence, these sophisticated molecular machines can be reprogrammed to respond to unnatural input signals. In this Review, we show how voltage-gated and ligand-gated ion channels can be endowed with synthetic photoswitches, and how the resulting artificial photoreceptors can be used to optically control neurons with exceptional temporal and spatial precision. They work well in animals and might find applications in the restoration of vision and the optical control of other sensations. The combination of synthetic photoswitches and receptor proteins contributes to the field of optogenetics and adds a new functional dimension to chemical genetics. As such, we propose to call it "optochemical genetics".

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Section: Reviewsmentioning

confidence: 99%

Section: Reviewsmentioning

confidence: 99%

Optochemical Genetics

Fehrentz¹,

Schönberger²,

Trauner³

2011

Angew Chem Int Ed

Self Cite

347

261

View full text Add to dashboard Cite

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“…S3). Domain closure is measured in terms of the 2-dimensional order parameter (1,2), where 1 is the distance between the center-of-mass of residues 517-519 (Lobe 1) and 689 -690 (Lobe 2), and 2 is the distance between residues 439 -441 (Lobe 1) and 721-722 (Lobe 2). ⌬12 is the difference in cleft closure for the closed LBD relative to the crystal structure of GluR6 bound to glutamate, where 12 ϭ (1ϩ2)/2.…”

Section: Simulations and Analysismentioning

confidence: 99%

“…Several naturally photosensitive channels and pumps have been cloned and used in a variety of biological preparations (1). In parallel, 3 classes of chemical-biological approaches have been used to obtain optical control over biological signaling: (i) free photolabile ''caged'' ligands, (ii) photoisomerizable (photochromic) free ligands (2), and (iii) photoswitched tethered ligands (PTLs) (3)(4)(5)(6). Of these, the most molecularly focused are the PTLs, which selectively attach to specific protein targets and exclusively endow them with sensitivity to light.…”

mentioning

confidence: 99%

Nanosculpting reversed wavelength sensitivity into a photoswitchable iGluR

Szobota

Lau

Gorostiza

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Photoswitched tethered ligands (PTLs) can be used to remotely control protein function with light. We have studied the geometric and conformational factors that determine the efficacy of PTL gating in the ionotropic glutamate receptor iGluR6 using a family of photoiosomerizable MAG (maleimide-azobenzene-glutamate) PTLs that covalently attach to the clamshell ligand-binding domain. Experiments and molecular dynamics simulations of the modified proteins show that optical switching depends on 2 factors: (i) the relative occupancy of the binding pocket in the 2 photoisomers of MAG and (ii) the degree of clamshell closure that is possible given the disposition of the MAG linker. A synthesized short version of MAG turns the channel on in either the cis or trans state, depending on the point of attachment. This yin/yang optical control makes it possible for 1 wavelength of light to elicit action potentials in one set of neurons, while deexciting a second set of neurons in the same preparation, whereas a second wavelength has the opposite effect. The ability to generate opposite responses with a single PTL and 2 versions of a target channel, which can be expressed in different cell types, paves the way for engineering opponency in neurons that mediate opposing functions.glutamate receptor ͉ ion channel ͉ optics ͉ photoswitch

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“…A large number of caged glutamate variants have been synthesized, including a reversibly caged glutamate [82] and a double-caged glutamate for slightly improved UV resolution at the expense of a higher power requirement [83][84][85]. A visible-light sensitive caged glutamate was first described in 2005 (DECM-glutamate) [86].…”

Section: Caged Neurotransmittersmentioning

confidence: 99%

Neocortical Layer 4 to Layer 2/3 Sensory Information Processing Investigated with Digital-Light-Projection Neuronal Photostimulation

Jerome¹

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Reversibly Caged Glutamate: A Photochromic Agonist of Ionotropic Glutamate Receptors

Abstract: The design, synthesis, and biological evaluation of a photochromic glutamate analogue is described. The molecule functions as a reversibly caged neurotransmitter and can be used to influence neural activity with light.

Cited by 157 publications

References 20 publications

Optochemical Genetics

Optochemical Genetics

Nanosculpting reversed wavelength sensitivity into a photoswitchable iGluR

Neocortical Layer 4 to Layer 2/3 Sensory Information Processing Investigated with Digital-Light-Projection Neuronal Photostimulation

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