Indicated are the intracellular steps of the Gq signaling cascade, which can now be controlled by scientists using light to drive activity in transgenic mouse hearts (left) and contractions in the small intestine (right). Source: Prof. Brügmann / umg.

A new tool for optogenetics: human receptor for studying cell function with light

Scientists of the University Medical Center Göttingen identify the human OPN5 receptor as a new target to activate cells and to study the principles of how cells communicate with each other. Published on 1 April 2022 in the renowned journal Nature Communications.

Gq proteins and the signaling cascade they trigger play an important role in all cells of our body: messengers bind to the cell membrane and activate intracellular proteins via so-called G protein-coupled receptors to control and direct cellular activities. This mechanism enables cells to adapt to the demands of the environment within an organ and the body. However, until now there has been little technical ability to study how information from outside the cell is transmitted and encoded by the receptor to the intracellular space across the membrane. This is mainly due to the lack of temporal and spatial precision of conventional methods.

Scientists from the Institute of Cardiovascular Physiology at the University Medical Center Göttingen (UMG) and the Cluster of Excellence Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells (MBExC) have now identified a new receptor to activate Gq proteins in cells with light. The receptor neuropsin or OPN5 is found in mammals and humans. Prof. Dr. Dr. Brügmann’s team first proved and demonstrated in simple cell systems that the receptor specifically responds to UV light (~380 nm), activates the Gq signaling cascade, and is highly sensitive to light. The scientists were able to exclude the activation of other signaling cascades. Performing studies on a transgenic mouse model, they also described potential applications in the heart, gastrointestinal tract, bladder and uterus. In these organs, smooth muscle cells are responsible for building up strength; thus, light can directly trigger contractions here. The scientists were able to observe the temporal relationships that play a role in this process and that here, too, as in skeletal muscle, individual muscle twitches can add up and thus increase overall strength.

The researchers’ findings open up new insights to better understand the role and function of OPN5 in humans. They also open up new approaches to elucidate the principles of how cells communicate with each other. The research results were published on 1 April 2022 in the renowned journal Nature Communications.

 

Original publication: Selective optogenetic control of Gq signaling using human Neuropsin. Ahmed Wagdi, Daniela Malan, Udhayabhaskar Sathyanarayanan, Janosch S. Beauchamp,Markus Vogt, David Zipf, Thomas Beiert, Berivan Mansuroglu, Vanessa Dusend, Mark Meininghaus, Linn Schneider, Bernd Kalthof, J. Simon Wiegert , Gabriele M. König, Evi Kostenis , Robert Patejdl, Philipp Sasse & Tobias Bruegmann. Nat Commun, 13, Article number: 1765 (2022). https://doi.org/10.1038/s41467-022-29265-w.

 

Research results in detail

“Using light as a stimulus, we can now mimic the effects of different pulse durations, intensities and repetition rates as they occur in living organisms,” says Prof. Dr. Dr. Tobias Brügmann, head of the research group Vegetative Optogenetics at the Institute of Cardiovascular Physiology (UMG), member of the MBExC and last author of the publication. “In addition, we can specifically express OPN5 in certain cell types and thus determine the impact of the Gq signaling cascade in these cells on organ function,” said Prof. Brügmann.

 

Function and application in cardiac research

In collaboration with scientists from the University of Bonn, the team around Prof. Brügmann demonstrated this possibility in the hearts of transgenic mice. In the heart, the Gq signaling cascade influences the heart rate and the strength of the heartbeat. “We are now able to use our tool to exactly study which kinetics underlie these physiological effects. We can moreover observe when they turn into pathological consequences and trigger diseases such as heart failure and cardiac arrhythmias,” says Ahmed Wagdi, MD student in Prof. Brügmann’s research group and now a resident in the Department of Cardiology and Pneumology at the UMG.

 

Application in the gastrointestinal tract

In addition, the scientists were able to show: Light can be used to generate contractions in organs with smooth muscle cells. This could open up a new approach for restoring food passage with light in patients suffering from movement disorders of the gastrointestinal tract in the future. “Until now, we only had light-sensitive proteins from one type of algae available for this therapeutic approach. Since OPN5 is commonly expressed in humans, the risk of a possible immune response against the therapeutic approach will be reduced,” says Prof. Brügmann. His research group currently works on the development of an optic gastric pacemaker and will next test the efficiency of OPN5 for this specific application.

 

Drug screening in the pharmaceutical industry

In a collaboration with the pharmaceutical company Bayer AG, the scientists used OPN5 and light stimulation in screening for new drugs. More than 200,000 substances were tested to determine their ability to block an intermediate step in the Gq signaling cascade. A classical approach with pharmacological activation resulted in over 3000 false-positive hits. In contrast, the approach using light did not result in a single false-positive hit. “We were thus able to show that our optogenetic approach fundamentally and decisively increases the efficiency of drug development. This is important since the validation of false-positive hits costs a lot of time and effort,” says Udhay Sathyanarayanan, also PhD student at the Institute of Cardiovascular Physiology at the UMG.

In addition to optogenetic applications in basic science and translational projects, there is another interesting prospect: “So far, we have only a relatively rudimentary idea and know that OPN5 is involved in the adaptation to daily rhythms in single organs, such as the eye, the skin or the brain. With our results, we can now better investigate and understand these roles in the future,” says Prof. Brügmann.

 

FURTHER INFORMATION

about the Brügmann Lab: https://hkp.umg.eu/en/research/vegetative-optogenetics/

Please download the PDF with the press release here:
Link to the UMG press release (in German)