Lights on the endocannabinoid system: Catching cellular membranes in action

Aurelien Laguerre, postdoctoral research fellow in the lab of Carsten Schultz, Ph.D., Department of Physiology and Pharmacology

For the pancreas to be healthy and operational, its individual cells need to communicate effectively with one another and synchronize their activities. Aurélien Laguerre, Ph.D., is looking at how endocannabinoid lipids participate in this synchronization. Manipulating these lipid molecules in living cells is fundamental to understand how they work, but their metabolism is so dynamic that this has been difficult to track in real-time. Aurélien, a postdoctoral research fellow in the lab of Carsten Schultz, Ph.D., is developing new light-responsive lipid tools that are making it possible to reveal these ultra-fast processes.

Oct 11, 2019 update: Laguerre is lead author on the Schultz lab’s new paper “Photorelease of 2-Arachidonoylglycerol in Live Cells,” published Sept. 27, 2019, in the Journal of the American Chemical Society.

What are you researching now—and why does it matter?

I am interested in the roles lipids play in the networks that cells use to communicate with one another. I’m especially interested in pancreatic β-cells, which are the cells secreting the insulin that helps with regulating our blood glucose concentration. It is important for these cells to quickly adapt their activity to glucose fluctuations in their environment. To be more efficient, cells have developed a complex system of communication relying on the exchange of small messengers. These messengers are molecules containing the information needed by the neighboring cell to synchronize its activity. We know that lipid molecules are important building blocks forming the membranes that separate the insides of cells from their surrounding environment. What is less known is how some of these lipids can also act as messengers and participate in this communication network.

It’s maybe easier to consider these messengers as tiny ‘keys’ able to unlock very specific ‘doors’ in the cell. Each ‘door opening’ will trigger a specific event that will inform the cell about its surrounding environment.  Here, the key we are interested in is a lipid called 2-arachidonoyl glycerol. This lipid is part of a family of messengers called endocannabinoids because it activates cannabinoid receptors naturally present in our β-cells. These cannabinoid receptors are the doors we are looking at. My objective is to understand how the action of the 2-arachidonoyl glycerol onto cannabinoid receptors plays a role in the communication between β-cells.

It’s a challenge to study lipids — they can’t be handled as easily as proteins or DNA, for example. They can’t be genetically encoded and even a small alteration of their chemical structures can trigger unwanted consequences in a cellular environment. Also, lipid metabolism is a highly dynamic process — in order to manipulate lipid levels in live cells, we have to develop new techniques that can compete with these fast fluctuations.

One of our strategies relies on designing molecular tools and testing a way to use light to control lipid levels in living cells. We call them ‘caged’ lipids. Coming back to our illustration, here we altered the shape of our key with a cap that can only be removed if we shed UV light on it — without light, the key cannot open its door anymore.

The idea behind this is we can feed the cells with these molecular tools without triggering any cellular events. With a simple flash of light, we can then suddenly release the messengers from inside of living cells and reveal the signaling activity of the lipid we are studying, in my case the 2-arachidonoyl glycerol. This technique allows us to reveal biological processes that could not be observed otherwise.

What’s been your most exciting moment in discovery?

It’s difficult to answer that, it’s actually difficult for me to pick only one of them! I would say it is maybe the first time I was able to control complex cellular events with a simple flash of light under a microscope.

For the first time, we were able to observe the photo-release process of our caged endocannabinoid inside the cells while monitoring β-cells activity in real time.

What’s your day-to-day life as a researcher look like?

When I am not at the fume-hood doing chemistry, you can find me in the dark room behind the microscope. Apart from that, my day-to-day life involves a lot of reading and certainly too much coffee. Working in chemical-biology offers the chance to evolve through a broad range of disciplines, from organic chemistry to cell biology. This helps keep me out of my comfort zone and always encourages me to learn new techniques and try new experiments. Every day is very different and I think this makes a researcher’s life even more exciting.

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