Taxi Photoswitch Knowing Neurons

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.

Healthy Retina vs Retinal DegnerationIn 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 geneA sequence of nucleic acids that forms a unit of genetic inh... More 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 NeuronThe functional unit of the nervous system, a nerve cell that... More, 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.

Photoisomerization

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.

Taxi

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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: 

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:

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

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Kate Fehlhaber

Kate graduated from Scripps College in 2009 with a Bachelor of Arts degree in Neuroscience, completing the cellular and molecular track with honors. As an undergraduate, she studied long-term plasticity in models of Parkinson’s disease in a neurobiology lab at University of California, Los Angeles. She continued this research as lab manager before entering the University of Southern California Neuroscience graduate program in 2011 and then transferring to UCLA in 2013. She completed her PhD in 2017, where her research focused on understanding the communication between neurons in the eye. Kate founded Knowing Neurons in 2011, and her passion for creative science communication has continued to grow.
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Kate Fehlhaber

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Kate graduated from Scripps College in 2009 with a Bachelor of Arts degree in Neuroscience, completing the cellular and molecular track with honors. As an undergraduate, she studied long-term plasticity in models of Parkinson’s disease in a neurobiology lab at University of California, Los Angeles. She continued this research as lab manager before entering the University of Southern California Neuroscience graduate program in 2011 and then transferring to UCLA in 2013. She completed her PhD in 2017, where her research focused on understanding the communication between neurons in the eye. Kate founded Knowing Neurons in 2011, and her passion for creative science communication has continued to grow.

One Comment

  1. So first I wanted to say Wow! What a genius idea, using light to heal pain! I wanted to ask- the chemical that can be used as a photo switch for pain- where would it be injected- into the eyes as well? And.when will this product be out there, available to the public?

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