How Azobenzene Photoswitches Restore Visual Responses to the Blind Retina.
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.
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Ivan
I
Tochitsky
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Zachary
Z
Helft
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Victor
V
Meseguer
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Russell B
RB
Fletcher
Department of Anatomy and Neuroscience, The University of Melbourne, Parkville 3010, VIC Australia.
Kirstan A
KA
Vessey
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Michael
M
Telias
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Bristol
B
Denlinger
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Jonatan
J
Malis
Department of Anatomy and Neuroscience, The University of Melbourne, Parkville 3010, VIC Australia.
Erica L
EL
Fletcher
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: rhkramer@berkeley.edu.
Richard H
RH
Kramer
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001391:Azo Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D001766:Blindness / Q000503:physiopathology; D007473:Ion Channels / Q000378:metabolism; D051379:Mice; D010775:Photic Stimulation; D010786:Photoreceptor Cells / Q000187:drug effects / Q000502:physiology; D010787:Photosensitivity Disorders / Q000139:chemically induced / Q000378:metabolism; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D058469:Receptors, Purinergic P2X / Q000096:biosynthesis / Q000502:physiology; D012160:Retina / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014785:Vision, Ocular / Q000187:drug effects* / Q000502:physiology*
D001391:Azo Compounds; D007473:Ion Channels; D017319:Photosensitizing Agents; D058469:Receptors, Purinergic P2X; C009850:azobenzene
P2X receptor; azobenzene; blindness; ion channel; photoswitch; retina; retinal degeneration; retinal ganglion cell; retinitis pigmentosa; vision
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