Die another day – when biology becomes a crime hunt

cell

I am a PhD student in Pharmacology. As I learnt over the past year, this can be a pretty good conversation killer. Except if people misunderstand you and are suddenly dying to know more about your project in “Farm Ecology”. Blame it on my French accent. After several social interaction disasters, I couldn’t help but wonder what is it in Pharmacology that puts people off?

If I refer to the etymology, Pharmacology comes from the Greek word pharmakon, which means poison, and logia, meaning study of. I can see that the study of poisons might sound a bit scary indeed. More realistically though, Pharmacology is the intersection of several areas of study. It connects physiology, pathology, chemistry, cellular and molecular biology, toxicology and many others. In an era of interdependent fields, Pharmacology is at the very centre.

My interest focuses on the role of P2X7. As much as it might sound like a super-secret-mission code, P2X7 is simply the name of a cellular receptor activated by the energy currency of the cell (ATP). The secret of P2X7 lies in its versatile ability to promote cellular death as well as growth. Whether we talk about cancer, inflammation, fibrosis, pain or diabetes, P2X7 seems to be part of the show. Actually, P2X7 sounds very much like the James Bond of the cell – although somewhat less sexy than Pierce Brosnan. And with this statement comes my first question: where is P2X7?

P2X7 has been found in different cell types, but predominantly in cells involved in the immune system. It is not so surprising to find the agent number 7 on the crime scene, but whereabouts exactly? Is it kindly waiting for its time in the antechamber (also known as endoplasmic reticulum for the biologists out there) or up front on the balcony (that would be the plasma membrane, for the enlightened)? And that is where the mystery kicks in. P2X7 has been found at the plasma membrane, aka the balcony. The receptor is structured as a channel through the plasma membrane, and in the presence of ATP, it will open and let ions pass through, allowing exchange between the extracellular and the intracellular environment. If the interaction with ATP is prolonged, the receptor dilates into a bigger pore, letting bigger molecules pass through and irreversibly leading to the death of the cell. However, P2X7 is not always at the plasma membrane but can be retained in the endoplasmic reticulum.

So what is the order that our Agent 7 needs to leave the antechamber for the balcony?

One of the particularities of P2X7 is its uniquely long intracellular tail. This James Bond accessory has been shown to be crucial for its mission assignment. A few tweaks to it and Agent 7 will lose itself in the kitchen or the dining room. Could it be that this accessory is the secret of P2X7? To answer this question, I transferred this accessory to an innocent cell character present in immune cells, and thus created what we call a chimera – a random someone with the James Bond accessory. This chimera allows me to study the properties imparted by the intracellular tail of P2X7. By doing so, it not only allows me to understand how to communicate with and assign my cellular James Bond to missions, but also what Bond needs to succeed. Surely, everyone will agree that James Bond would not be James Bond without his Bond Girls. And that is my next question: who is the James Bond Girl?

There are plenty of attractive molecules out there willing to interact with James Bond, and the hypothesis that the charm of the famous Agent 7 lies in its intracellular tail has been mentioned more than once. My chimera represents then a way to trap James Bond Girl candidates. I can meet the girls and ask them what it is that is so irresistible in P2X7.

Surely, all the mysteries of James Bond are far too complex to be fully understood, but the end of our crime hunt might well be the discovery of a tool that will allow us to make cells die another day.

*Marie Brunet [2011] is doing a PhD in Pharmacology. Picture credit: Dream designs and http://www.freedigitalphotos.net.

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