Restoring Light Sensitivity in Blind Retinae Using a Photochromic AMPA Receptor Agonist

ACS Chem Neurosci. 2016 Jan 20;7(1):15-20. doi: 10.1021/acschemneuro.5b00234. Epub 2015 Nov 3.

Abstract

Retinal degenerative diseases can have many possible causes and are currently difficult to treat. As an alternative to therapies that require genetic manipulation or the implantation of electronic devices, photopharmacology has emerged as a viable approach to restore visual responses. Here, we present a new photopharmacological strategy that relies on a photoswitchable excitatory amino acid, ATA. This freely diffusible molecule selectively activates AMPA receptors in a light-dependent fashion. It primarily acts on amacrine and retinal ganglion cells, although a minor effect on bipolar cells has been observed. As such, it complements previous pharmacological approaches based on photochromic channel blockers and increases the potential of photopharmacology in vision restoration.

Keywords: AMPA receptors; ATA; Photopharmacology; photochromic ligand; retinal degeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Animals
  • Animals, Newborn
  • Blindness / drug therapy*
  • Blindness / genetics
  • Blindness / pathology
  • Cyclic Nucleotide-Gated Cation Channels / deficiency
  • Cyclic Nucleotide-Gated Cation Channels / genetics
  • Disease Models, Animal
  • GABA Agents / pharmacology
  • GluK2 Kainate Receptor
  • HEK293 Cells
  • Hippocampus / cytology
  • Humans
  • Light*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / drug effects
  • Neurons / physiology
  • Phosphinic Acids / pharmacology
  • Picrotoxin / analogs & derivatives
  • Picrotoxin / pharmacology
  • Pyridines / pharmacology
  • Receptors, AMPA / metabolism*
  • Receptors, Kainic Acid / genetics
  • Receptors, Kainic Acid / metabolism*
  • Retinal Ganglion Cells / drug effects
  • Retinal Ganglion Cells / physiology*
  • Rod Opsins / deficiency
  • Rod Opsins / genetics
  • Sesterterpenes
  • rho GTP-Binding Proteins / deficiency
  • rho GTP-Binding Proteins / genetics

Substances

  • (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid
  • Cnga3 protein, mouse
  • Cyclic Nucleotide-Gated Cation Channels
  • GABA Agents
  • Gluk1 kainate receptor
  • Phosphinic Acids
  • Pyridines
  • Receptors, AMPA
  • Receptors, Kainic Acid
  • Rod Opsins
  • Sesterterpenes
  • melanopsin
  • Picrotoxin
  • picrotoxinin
  • rho GTP-Binding Proteins