Newly discovered chemical reaction in eye may improve vision

April 5, 2017
Credit: CC0 Public Domain

A light-sensing pigment found in everything from bacteria to vertebrates can be biochemically manipulated to reset itself, an important therapeutic advantage, according to new research out of Case Western Reserve University School of Medicine. In a study just released from the Proceedings of the National Academy of Sciences, researchers successfully used a modified form of vitamin A, called locked retinal, to induce the recycling mechanism and engage proteins central to human vision. The targeted proteins include light-sensing rhodopsin, which belongs to a family of proteins—G protein-coupled receptors, or GPCRs—that sit in cell membranes and transmit external cellular cues into internal cell signaling pathways. The discovery opens a new therapeutic opportunity for modified retinals that help improve vision, and offers a major improvement over current therapeutics designed to perturb cell signaling in the eye.

"Our study demonstrates a complete transition from a one-way activation of a GPCR into a self-renewing, recycling activation mechanism by the mere addition of a cyclohexyl chemical group to the retinal. These findings exemplify the possibility of reprogramming GPCRs into self-renewing machines that can be controlled by external cues. This biochemically induced function will be helpful in treating people with vision impairment, and opens up several avenues for more efficient GPCR-based therapeutics," said Sahil Gulati, first author of the study and graduate student in the department of pharmacology at Case Western Reserve University School of Medicine. Krzysztof Palczewski PhD, professor and chair of the department, served as senior author for the study.

The discovery digs into the biochemistry of vision and why the chemical configuration of the retinal is critical for humans to perceive . Humans see with the help of an extremely sensitive in the back of the eye called rhodopsin, which attaches to a retinal molecule to sense light. Light photons enter the eye and get absorbed by the retinal-rhodopsin complex, activating a cascade of downstream signals that constitute vision. Importantly, the retinal awaits light photons while maintaining a particular chemical configuration—11-cis retinal—and transforms into a second configuration—all-trans retinal—after it absorbs a light photon. But this transformation is a one-way ticket, and requires an army of specialized proteins to convert all-trans-retinal back to 11-cis-retinal. Inherited mutations in any of these specialized proteins can cause retinal degenerative diseases. Researchers who want to treat such diseases must repair or bypass the mutated proteins to maintain this retinal conversion in humans.

"Our study shows how a chemical modification in the retinal can activate downstream visual signaling in a photocyclic manner. This chemical modification allows retinal to self-renew using thermal energy, and hence does not require any additional enzymes," Gulati said.

The researchers discovered the self-renewing mechanism in bovine rhodopsin, which is exceptionally similar to human rhodopsin. The researchers used purified proteins in their laboratory to show that their modified retinal binds to bovine rhodopsin and successfully activates specific human eye proteins in response to light, and when complete, it uses thermal energy to slowly return to its inactive form that can be repeatedly reactivated with light. The findings suggest that retinal molecules with the specific chemical structure could reversibly stimulate rhodopsin that drives human vision.

Said Gulati, "Although one-way reaction mechanisms of GPCRs enable them to function normally in the human body, they cannot renew their activator molecules, and hence are dependent on continuous administration of drug molecules to treat disease symptoms. Controlled cyclic activation of GPCRs makes them self-sustainable."

The newly discovered mechanism may enhance current approaches to treat and other nerve cell disorders. Researchers can biochemically tinker with the retinal and the retinal-bound molecules to improve their ability to turn on and off proteins in the eye. Said Gulati, "Our next steps will be to design a new class of modified retinals with faster thermal recovery, and to test their efficiency as human therapeutic modalities."

Explore further: Visual pigment rhodopsin forms two-molecule complexes in vivo

More information: Sahil Gulati et al, Photocyclic behavior of rhodopsin induced by an atypical isomerization mechanism, Proceedings of the National Academy of Sciences (2017). DOI: 10.1073/pnas.1617446114

Related Stories

Visual pigment rhodopsin forms two-molecule complexes in vivo

July 25, 2016
The study of rhodopsin—the molecule that allows the eye to detect dim light—has a long and well-recognized history of more than 100 years. Nevertheless, there is still controversy about the structure in which the molecule ...

Scientists find that stem cell exosomes promote survival of retinal ganglion cells in rats

January 27, 2017
A new study in rats shows that stem cell secretions, called exosomes, appear to protect cells in the retina, the light-sensitive tissue in the back of the eye. The findings, published in Stem Cells Translational Medicine, ...

Potential new approaches to treating eye diseases

February 4, 2016
Potential new approaches to treating eye diseases such as age-related macular degeneration (AMD) are described in a new study, "IL-33 amplifies an innate immune response in the degenerating retina," in the February Journal ...

New insight into eye diseases

September 28, 2016
Many diseases that lead to blindness, such as glaucoma and macular degeneration, are caused by the death of certain cells in the human retina that lack the ability to regenerate. But in species such as zebrafish these cells, ...

New research could lead to restoring vision for sufferers of retinal disorders

June 29, 2016
Engineers and neuroscientists at the University of Sheffield have demonstrated for the first time that the cells in the retina carry out key processing tasks. This could pave the way for improving retinal implants and therefore ...

Light in sight: A step towards a potential therapy for acquired blindness

May 7, 2015
Hereditary blindness caused by a progressive degeneration of the light-sensing cells in the eye, the photoreceptors, affects millions of people worldwide. Although the light-sensing cells are lost, cells in deeper layers ...

Recommended for you

Curve-eye-ture: How to grow artificial corneas

October 19, 2017
Scientists at Newcastle University, UK, and the University of California have developed a new method to grow curved human corneas improving the quality and transparency - solely by controlling the behaviour of cells in a ...

Clinical study success for novel contact lens device aimed to improve glaucoma treatment

October 19, 2017
A novel contact lens device developed by University of Liverpool engineers to improve the treatment of glaucoma has been found to reliably track pressure changes in the eye and be wearable by people who took part in its first ...

Study indicates proof of concept for using a surrogate liquid biopsy to provide genetic profile of retinoblastoma tumors

October 12, 2017
Retinoblastoma is a tumor of the retina that generally affects children under 5 years of age. If not diagnosed early, retinoblastoma may result in loss of one or both eyes and can be fatal. Unlike most cancers that are diagnosed ...

Farsighted children struggle with attention, study finds

October 10, 2017
Farsighted preschoolers and kindergartners have a harder time paying attention and that could put them at risk of slipping behind in school, a new study suggests.

New drug reduces rate of progression of incurable eye disease

October 4, 2017
An international study including researchers from the Centre for Eye Research Australia (CERA) has found a way to slow the progression of dry age-related macular degeneration (AMD) - one of the most common causes of vision ...

Gene therapy shows promise for reversing blindness

October 2, 2017
Most causes of untreatable blindness occur due to loss of the millions of light sensitive photoreceptor cells that line the retina, similar to the pixels in a digital camera.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.