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Review
. 2015 Feb:20:135-43.
doi: 10.1016/j.coph.2014.12.008. Epub 2015 Jan 5.

Controlling ionotropic and metabotropic glutamate receptors with light: principles and potential

Andreas Reiner  1 , Joshua Levitz  1 , Ehud Y Isacoff  2
Affiliations
Review

Controlling ionotropic and metabotropic glutamate receptors with light: principles and potential

Andreas Reiner et al. Curr Opin Pharmacol. 2015 Feb.

Abstract

Light offers unique advantages for studying and manipulating biomolecules and the cellular processes that they control. Optical control of ionotropic and metabotropic glutamate receptors has garnered significant interest, since these receptors are central to signaling at neuronal synapses and only optical approaches provide the spatial and temporal resolution required to directly probe receptor function in cells and tissue. Following the classical method of glutamate photo-uncaging, recently developed methods have added other forms of remote control, including those with high molecular specificity and genetic targeting. These tools open the door to the direct optical control of synaptic transmission and plasticity, as well as the probing of native receptor function in intact neural circuits.

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Conflict of interest statement

Conflict of Interest: The authors have no conflict of interest.

Figures

Figure 1
Figure 1. Functional diversity of ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs)
(a) GluRs and pharmacology: iGluRs are tetrameric ion channels (left) and mGluRs are dimeric G protein-coupled receptors (right). Heteromerization within different subfamilies increases the functional diversity of iGluRs and mGluRs further. (b) iGluRs and mGluRs occur pre- and postsynaptically, where they play multiple roles in signal transmission, the control of neurotransmitter release and regulation of synaptic strength. They are also found in extrasynaptic locations and glial cells, highlighting their regulatory functions.
Figure 2
Figure 2. Approaches to optically control glutamate receptor signaling
(a) Photo-uncaging of ligands that are masked with photo-labile protecting groups. (b) Photo-inactivation of receptors with photoreactive ligands (ANQX) or after incorporation of photo-reactive amino acids (Azp, Bzp). (c) Photoswitchable ligands that can be reversibly switched between high and low affinity states. Azobenzene derivatives, which can be photoisomerized between trans and cis configurations, commonly serve as photoswitches. GluAzo is a photoswitchable glutamate derivative, ATA3 an AMPAR agonist and Alloswitch-1 a mGluR5 negative allosteric modulator (NAM). (d) Photoswitchable tethered ligands (PTLs) are covalently attached to genetically engineered receptor subunits. For GluRs, MAG ligands are used, which encompass a maleimide group for covalent attachment to cysteine residues, a central azobenzene photoswitch and a 4-alkyl glutamate ligand. Details are described in the text.
Figure 3
Figure 3. Optical control of LiGluR and LimGluRs with photoswitchable tethered ligands
(a,b) LiGluR photoswitching after labeling of GluK2(L439C) with L-MAG0. Illumination with ∼380 nm light (violet bar) isomerizes MAG to the cis configuration, which results in receptor activation as demonstrated in HEK cell voltage-clamp recordings. Illumination with ∼500 nm light (green bar) reverses MAG to its trans configuration and causes receptor deactivation. (a) Reversible LiGluR photoswitching recorded in the presence of concanavalin A to suppresses desensitization. Regular MAG is ‘bistable’ since it stays in the cis state for minutes after the light is turned off (grey bar). (b) Fast photoswitching (100 μs light pulse with high intensity) leads to receptor activation in less than a millisecond and concomitant desensitization (τdesen = 4 ms), which resembles receptor gating induced by brief pulses of glutamate (from Reiner et al. [32]). (c) LimGluR2 photo-agonism obtained with D-MAG0 labeling at L300C. Gβγ-mediated activation of coexpressed GIRK1 channels was used as a read-out of mGluR2 activation (for details see Levitz et al. [29]). (d) LimGluR2 photo-antagonism obtained with D-MAG0 labeling at S302C. At this position cis-MAG suppresses glutamate-induced activation of mGluR2 (from [29]).
Figure 4
Figure 4. Optical control of GluRs for studying synapses and circuits
(a) The expression of photoswitchable glutamate receptors can be targeted to the presynaptic, postsynaptic, or glial compartments for studying their role in synaptic signaling. (b) Expression and MAG-labeling of LimGluR2 in autaptic hippocampal neurons allows for light-induced presynaptic inhibition and manipulation of short-term plasticity. LimGluR2 activation (380 nm, violet bar) increases the paired pulse ratio (pulse 2/pulse 1) of evoked EPSCs confirming the presynaptic origin of the effect (from Levitz et al. [29]). (c) Repeated photoactivation of LiGluR in cultured cortical astrocytes produces large, reliable Ca2+–transients that can initiate gliotransmitter release (from Li et al. [38]). (d) Postsynaptic activation of LiGluR expressed in the muscle of the drosophila neuromuscular junction showed that postsynaptic iGluRs can enhance recovery from synaptic depression pointing to a retrograde signaling mechanism (from Kauwe et al. [37]). (e) In vivo 2-photon uncaging of MNI-glutamate at single dendritic spines in mouse cortex demonstrates the spatial and temporal precision afforded by optical activation of glutamate receptors (from Noguchi et al. [7]). (f) Targeted expression of LiGluR (UAS:LiGluR) to the Gal4s1003t in larval zebrafish allowed for the optical induction of a swim response and subsequent identification of key neurons involved in the swim circuit (from Wyart et al. [42]).
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