Flipping the Photoswitch: Ion Channels Under Light Control

Abstract

Nature has incorporated small photochromic molecules, colloquially termed 'photoswitches', in photoreceptor proteins to sense optical cues in phototaxis and vision. While Nature's ability to employ light-responsive functionalities has long been recognized, it was not until recently that scientists designed, synthesized and applied synthetic photochromes to manipulate biological processes with the temporal and spatial resolution of light. Ion channels in particular have come to the forefront of proteins that can be put under the designer control of synthetic photochromes.Photochromic ion channel controllers are comprised of three classes, photochromic soluble ligands (PCLs), photochromic tethered ligands (PTLs) and photochromic crosslinkers (PXs), and in each class ion channel functionality is controlled through reversible changes in photochrome structure. By acting as light-dependent ion channel agonists, antagonist or modulators, photochromic controllers effectively converted a wide range of ion channels, including voltage-gated ion channels, 'leak channels', tri-, tetra-and pentameric ligand-gated ion channels, and temperaturesensitive ion channels, into man-made photoreceptors. Control by photochromes is reversible, unlike in the case of 'caged' compounds, and non-invasive with high spatial precision, unlike pharmacology and electrical manipulation. Here, we introduce design principles of emerging photochromic molecules that act on ion channels and discuss the impact that these molecules are beginning to have on ion channel biophysics and neuronal physiology.

Two-Photon Excitation of Azobenzene Photoswitches for Synthetic Optogenetics

“…Despite progresses made since the very first demonstrations of Synthetic optogenetics by the Erlanger group in the late 1960s [19,32], current illumination schemes remain as they were back then, namely rely on the use of visible light, typically near-UV (~400 nm) for trans-to-cis photoisomerization and blue-shifted wavelengths (~500) for cis-to-trans [9,12,15,17,18,24,33,34]. Aside the potential cytotoxicity of these wavelengths [35,36], visible light is not well-suited for deep tissue penetration due to strong absorption and scatter from endogenous components [37].…”

Optogenetics and photopharmacology in pain research and therapeutics

“…Voltage-gated ion channels (VGICs) play an essential role in the generation of action potentials and in synaptic transmission and represent a privileged target of photopharmacology. They have also been fundamental for the development of the field (132). The photoswitchable azobenzene derivative QAQ is structurally composed of two azo-linked quaternary amines and, together with its derivative QX-314, has been developed on the basis of lidocaine, a local anaesthetic that blocks VGICs (133,134).…”

Characterization of DAG Binding to TRPC Channels by Target-Dependent cis–trans Isomerization of OptoDArG

“…Recent advances in lipid photopharmacology enabled new insights into lipid signaling pathways, protein–lipid interactions, and the identification of lipid binding sites in signaling molecules [ 1 , 2 , 3 ]. This strategy of attaining control over biological functions with exceptional spatiotemporal precision using light-induced isomerization of synthetic photochromes has been developed over the past decade, and its value for biology and medicine is increasingly recognized [ 4 , 5 , 6 , 7 ].…”