Neuron
Volume 92, Issue 1, 5 October 2016, Pages 100-113
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Article
How Azobenzene Photoswitches Restore Visual Responses to the Blind Retina

https://doi.org/10.1016/j.neuron.2016.08.038Get rights and content
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Highlights

  • Functional changes in RGCs allow photoswitch compounds to act on the degenerating retina

  • Photoswitch entry into RGCs depends on functional upregulation of P2X receptors

  • Photocontrol of spiking for some photoswitches depends on changes in HCN channels

  • Photosensitization is highly selective for OFF-RGCs

Summary

Azobenzene photoswitches confer light sensitivity onto retinal ganglion cells (RGCs) in blind mice, making these compounds promising candidates as vision-restoring drugs in humans with degenerative blindness. Remarkably, photosensitization manifests only in animals with photoreceptor degeneration and is absent from those with intact rods and cones. Here we show that P2X receptors mediate the entry of photoswitches into RGCs, where they associate with voltage-gated ion channels, enabling light to control action-potential firing. All charged photoswitch compounds require permeation through P2X receptors, whose gene expression is upregulated in the blind retina. Photoswitches and membrane-impermeant fluorescent dyes likewise penetrate through P2X receptors to label a subset of RGCs in the degenerated retina. Electrophysiological recordings and mapping of fluorescently labeled RGC dendritic projections together indicate that photosensitization is highly selective for OFF-RGCs. Hence, P2X receptors are a natural conduit allowing cell-type-selective and degeneration-specific delivery of photoswitches to restore visual function in blinding disease.

Keywords

blindness
vision
retina
retinal ganglion cell
retinitis pigmentosa
retinal degeneration
photoswitch
azobenzene
ion channel
P2X receptor

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