Light now in sight: Control of a 'blind' neuroreceptor with an optical switch

Jan 10, 2012

When nerve cells communicate with one another, specialized receptor molecules on their surfaces play a central role in relaying signals between them. A collaborative venture involving teams of chemists based at Ludwig-Maximilians-Universitat (LMU) in Munich, Germany, and the University of California in Berkeley has now succeeded in converting an intrinsically "blind" receptor molecule into a photoreceptor. They achieved this feat by using molecular genetic techniques to attach what amounts to a light-controlled chemical "switch" to a macromolecular receptor that is normally activated by the endogenous neurotransmitter acetylcholine.

Dirk Trauner, Professor of Chemical Biology and Genetics at LMU Munich, who played a leading role in the project, hopes that the synthetic construct will help to elucidate the precise roles of the natural receptor in the brain. Indeed, he says that it might ultimately be possible to use such synthetic photoreceptors to restore sight to patients suffering from certain forms of blindness.

Trauner and his colleagues chose one of the so-called nicotinic acetylcholine receptors for their experiments. These molecular machines transmit essentially by converting an incoming into an electrical response, which is propagated along the length of the . They are found in many types of excitable cells in the nervous system, and at the so-called "endplates" which form the functional connections between and the that control them. Such receptors span the cell membrane, forming a physical link between the external medium and the interior of the cell. Binding of the to the external surface of the receptor acts as a switch, opening a tiny pore in the receptor, through which positively charged can flow into the cell. The resulting depolarization (change in the balance between positive and negative charges on either side of the membrane) gives rise to the so-called action potential, the basic electrical stimulus that constitutes the neural response.

The functional features of neuroreceptors make them attractive targets for a research strategy that Trauner calls "optochemical genetics." This involves the use of genetic manipulation to modify a receptor protein so that it can bind a synthetic, light-sensitive switching ligand. Compounds known as azobenzenes can serve as the basis for such switching elements. They contain a photosensitive double bond between nitrogen atoms, and can be flipped between bent and extended conformations by illumination with monochromatic light of different wavelengths. In order to ensure that the artificial switch attaches at the correct position, and that the light-induced conformational changes are sufficient to open and close the ion channel, Trauner and his colleagues introduced several targeted modifications into the gene that specifies the amino acid sequence of the receptor. Using electrophysiological techniques, they were able to confirm that cultured cells expressing the mutated gene responded in the expected manner. Following incubation of the cells with the appropriate azobenzene compound, illumination with violet light was shown to activate the modified receptor, while subsequent exposure to green light closed its ion channel.

In 2010 Dirk Trauner received one of the highly endowed Advanced Grants awarded by the European Research Council (ERC) for a project which is also based on a "photopharmacological" approach. Its long-term goal is to find ways of compensating for the loss of dedicated photoreceptors in the eye – the most common cause of blindness. To achieve this goal, Trauner is working on the development of hybrid photoreceptors. "The basic idea, which has in principle been shown to work in animal models, is to confer light sensitivity on surviving neurons in the eye that do not normally respond to light," he says.

Explore further: Research team announces new class of compounds that appear to be effective against malaria

More information: Optochemical control of genetically targeted neuronal nicotinic acetylcholine receptors, I. Tochitsky, M.R. Banghart, A. Mourot, J.Z. Yao, B. Gaub, R.H. Kramer, D. Trauner, Nature Chemistry, Jan 8, 2012. doi:10.1038/NCHEM.1234

Related Stories

Probing the secrets of the ryegrasses

Jun 20, 2011

Loline alkaloids protect plants from attack by insects and have other interesting features that have yet to be studied in detail. Chemists from Ludwig-Maximilians-Universitaet in Munich, Germany, have developed a method for ...

Complex channels

Jan 24, 2007

The messages passed in a neuronal network can target something like 100 billion nerve cells in the brain alone. These, in turn communicate with millions of other cells and organs in the body. How, then, do whole cascades ...

Controlling movements with light

Jul 20, 2011

German researchers at the Ruhr-Universitaet have succeeded in controlling the activity of certain nerve cells using light, thus influencing the movements of mice. By changing special receptors in nerve cells of the cerebellum ...

Recommended for you

Molecules that came in handy for first life on Earth

Nov 24, 2014

For the first time, chemists have successfully produced amino acid-like molecules that all have the same 'handedness', from simple building blocks and in a single test tube. Could this be how life started. ...

User comments : 0

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.