Thursday, October 11, 2012

Smart receptors on cell surfaces

10 October 2012

Your body is a fine-tuned system of interactions between billions of cells. Each cell has tiny receptors that enable it to sense its environment, so it can adapt to new situtations. Robert Lefkowitz and Brian Kobilka are awarded the 2012 Nobel Prize in Chemistry for groundbreaking discoveries that reveal the inner workings of an important family of such receptors: G-protein–coupled receptors.

Around 800 GPCRs are known to exist in humans and they regulate such diverse processes as smell, taste and light sensing © Science Photo Library

For a long time, it remained a mystery how cells could sense their environment. Scientists knew that hormones such as adrenalin had powerful effects: increasing blood pressure and making the heart beat faster. They suspected that cell surfaces contained some kind of recipient for hormones. But what these receptors actually consisted of and how they worked remained obscured for most of the 20th Century.

Lefkowitz started to use radioactivity in 1968 in order to trace cells' receptors. He attached an iodine isotope to various hormones, and thanks to the radiation, he managed to unveil several receptors, among those a receptor for adrenalin: β-adrenergic receptor. His team of researchers extracted the receptor from its hiding place in the cell wall and gained an initial understanding of how it works.

The team achieved its next big step during the 1980s. The newly recruited Kobilka accepted the challenge to isolate the gene that codes for the β-adrenergic receptor from the gigantic human genome. His creative approach allowed him to attain his goal. When the researchers analyzed the gene, they discovered that the receptor was similar to one in the eye that captures light. They realized that there is a whole family of receptors that look alike and function in the same manner.

Today this family is referred to as G-protein–coupled receptors. About a thousand genes code for such receptors, for example, for light, flavour, odour, adrenalin, histamine, dopamine and serotonin. About half of all medications achieve their effect through G-protein–coupled receptors.

The studies by Lefkowitz and Kobilka are crucial for understanding how G-protein–coupled receptors function. Furthermore, in 2011, Kobilka achieved another break-through; he and his research team captured an image of the β-adrenergic receptor at the exact moment that it is activated by a hormone and sends a signal into the cell. This image is a molecular masterpiece – the result of decades of research.

Sara Snogerup Linse from Lund University in Sweden explained the significance of the work. ‘G-protein coupled receptors sit in cell membranes. It’s their job to tell the inside of the cell what is going on outside. Thanks to the work of Lefkowitz and Kobilka, we know about what they are, how they are built and how they work.’

This family of receptors is important for numerous reasons. There are around 800 known human GPCRs, of which about half are the olfactory receptors that allow us to distinguish thousands of different aromas. The other half regulate a vast number of biological processes, each one interacting with multiple different signalling molecules to transmit different messages into the cell, based on where they are in the body and what has bound to them.

‘G-protein-coupled receptors are ubiquitous in the function of cells in the body and help us to sense light, flavour and odour. They are also responsible for the human body’s reactions to chemicals such as adrenaline, histamine, dopamine and serotonin – which are associated with medical conditions such as allergies, depression and Parkinson’s disease,’ said David Phillips, the immediate past-president of the RSC. ‘But before Lefkowitz identified them and, together with Kobilka, determined how they work, nobody even knew they existed.’

Studies of G-protein-coupled receptors

Source: The Royal Swedish Academy of Sciences ( & Royal Society of Chemistry

No comments: