Turning On A “Photoswitch” Helps Blind Mice See The Light

Our senses connect us to the world.  Your visual system lets you know that there is a yellow car ahead of you, and your auditory system lets you know that it is honking its horn.  As unique as each sensory system seems, they actually share basic characteristics and similarities of structure and function.  Beginning with a stimulus (the vision of the car or the sound of the horn), a cascade of complex interactions occurs that send signals through neural circuits so that we can respond to our surroundings.

In the visual system, this first step of transduction can be impeded, disabling sight in its entirety.  For example, progressive degeneration of photoreceptors, the cells in the retina that respond to light, causes blinding diseases like retinitis pigmentosa and age-related macular degeneration.  Even though the innermost layer of retinal cells, called ganglion cells, remains connected to the brain, they no longer transmit information useful for vision.  Currently, there is no way to reverse this degeneration, but there are major efforts in vision research to develop treatments.  Some researchers have focused on implantable devices, called retinal prostheses, which stimulate the surviving ganglion cells in a way that mimics the visual scene to partially restore vision.  Other researchers are using stem cell and gene therapies to repair the degenerating retina.  Now, a novel drug strategy could hold the future of retinal degeneration therapeutics.

A team of researchers led by Richard Kramer at the University of California, Berkeley collaborated with another team of scientists at Ludwig-Maximilians-Universitaet in Munich led by Dirk Trauner to develop a chemical “photoswitch” called DENAQ.  This method allows normally light-insensitive ganglion cells to respond to light.  In the latest issue of Neuron, the team reports that a single injection of DENAQ into the eyes of blind mice photosensitizes the blind retina for days, restoring electrophysiological and behavioral responses with no toxicity.  That’s right!  The “photoswitch” restored light responsiveness to a retina that had lost its primary photoreceptive cells!

So, how do you make a light-sensitive switch like DENAQ?  The secret lies in its chemical structure.  DENAQ contains a characteristic chemical bond that can be altered by light.  More specifically, light causes this bond to switch from its trans configuration to its cis configuration, a process called photoisomerization.  This process is very similar to how we see as exposure to light causes a cis to trans change in configuration of the molecule retinal.  In either case, photoisomerization causes a channel to open, so the cell becomes excited.  With this property, DENAQ can modify the behavior of ion channels expressed in cells to make them respond to light.

Beyond the visual system, these “photoswitches” can also be used to treat chronic pain syndromes.  In order to provide analgesia, your body makes endorphins, which bind to opioid receptors, G-protein coupled receptors (GCPRs), that activate downstream mechanisms to provide pain relief.  Trauner and his team chemically modified a particular type of opioid receptor so that it became photosensitive, thus providing pain-killing effects with light.

Because many of our senses, like vision, hearing, and taste, depend on the activity of different GPCRs, using these “photoswitches” may provide a new insight into the functions of this very important class of receptors.  Even more exciting is the prospect of using chemical “photoswitches” like DENAQ to treat many other neurological disorders and diseases.

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References:

Schönberger M. & Trauner D. (2014). A Photochromic Agonist for μ-Opioid Receptors, Angewandte Chemie International Edition, n/a-n/a. DOI: 10.1002/anie.201309633

Tochitsky I., Polosukhina A., Degtyar V., Gallerani N., Smith C., Friedman A., Van Gelder R., Trauner D., Kaufer D. & Kramer R. & (2014). Restoring Visual Function to Blind Mice with a Photoswitch that Exploits Electrophysiological Remodeling of Retinal Ganglion Cells, Neuron, 81 (4) 800-813. DOI: 10.1016/j.neuron.2014.01.003

Images adapted from Wikimedia Commons, uptodate.com, and icanhasscience.