Shedding new light on how adrenaline works

You slump down in to the seat, sweating, heart pounding. It was a bit of a sprint but you made the last bus. There’s adrenaline coursing through your veins but the last thing on your mind is how that adrenaline acts. A breakthrough paper published recently on line in Nature (http://www.nature.com/nature/journal/vnfv/ncurrent/full/nature10361.html) now sheds considerable light on the machinery in cells whereby the “fight or flight” hormone adrenaline works. Brian Kobilka and colleagues from Stanford University with collaborator Roger Sunahara from the University of Michigan have determined the atomic structure of an important site of action of adrenaline in its “on” state. This is one of the most significant findings in pharmacology for many years.

Adrenaline, a hormone released from the adrenal gland to influence many aspects of physiology, is a prototype for the vast array of signals that humans are able to detect. Other examples of signals that we detect are smells, tastes, vision and the myriad chemicals (neurotransmitters) in the brain and hormones in other parts of the body that influence our behaviour. The surprising conclusion of years of work in many labs has been that signal detection in all of these examples is based on a common principle. In each case, there is a signal and a detector protein, termed a receptor, with the ability to recognise that specific signal and react to it. The receptor collaborates with a transducer termed a G protein (named for its ability to bind a molecule abbreviated as GTP). The receptor and G protein together sit in the membrane of a cell providing a signalling machine. The signal molecule from the outside of the cell attaches to the receptor and activates the G protein sending a chemical stimulus to the inside of the cell and altering its activity.

Not only do we find this common principle of signal/receptor/G protein for many signalling systems but the receptors are also the sites of action of a third or more of currently prescribed drugs including many best sellers. For example, drugs used to treat high blood pressure, asthma, schizophrenia and Parkinson’s disease act via these kinds of receptors. Some illegal drugs such as cannabis and morphine also target this class of receptor. If you are still not convinced of the importance of these receptors then bear in mind that if you are drinking coffee or tea while reading this, the caffeine in these drinks is also acting via one of these receptors.

What Brian Kobilka and his team at Stanford did was to develop methods for making large amounts of one of these receptors which he then persuaded to form crystals so that he could analyse the atomic structure using X-rays. This was a heroic effort over about twenty years and resulted in 2007 in the structure of the receptor for adrenaline in its “off” state. Kobilka’s methods were then applied successfully to other receptors by other labs.

Now, four years later, Kobilka has the structure of the receptor and G protein in the “on” state. Comparison of the “on” and “off” structures allows us to understand how the signalling machine changes when it is switched on. This is an immense tour de force and Kobilka should be applauded.

This is a significant moment for those who have worked in this field, like myself. Many labs have spent years examining the receptors and the G proteins using indirect methods and to see finally a picture of the two key components of these signalling machines is quite awe inspiring. It’s like seeing the face of an old friend after a long time.

The implications of the work are also immense. We now have structures of the “on” and “off” states of these systems and can see how the proteins change when the system switches on. The receptor itself changes structure as you would predict but there are unexpectedly large changes in structure in parts of the G protein. This is the beginning of understanding how these signalling machines work at the atomic level. Given the uniformity of organisation in this signalling family, these conclusions are likely to be widely applicable to other receptors.

It is, however, in the area of drug design that the important practical implications of this work lie. There have been major advances in using atomic structures of proteins to design new drugs and the “off” structures of these receptors have already been used to pinpoint new potential drug families. The same analysis will now be applied to identify new drugs that put the receptor in to its “on” state. Some of these are likely to be applicable to therapy of asthma.

Several Nobel prizes have been awarded in the past to scientists working on these receptors linked to G proteins. The name of Brian Kobilka seems likely to be added to that list in the not too distant future.

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