"BOO!" Startling the crowd at a press conference in Stockholm, Sweden, was how Sven Lidin of the Nobel committee demonstrated the importance of work by the winners of this year's Nobel prize in chemistry. Robert Lefkowitz at the Howard Hughes Medical Institute in Durham, North Carolina, and Brian Kobilka at Stanford University in California were recognised for their work on G-protein-coupled receptors (GPCRs).
Lidin explained how the adrenaline rush and the associated "fight or flight response" that occur when we are startled is just one of the many signalling pathways that these receptors control.
For a long time, how cells could sense their environment remained a mystery, though many believed it was down to receptors hidden in the cell wall. In 1968, Lefkowitz was the first to demonstrate their existence, unveiling them using radioactive markers. Later he also extracted them from the cell wall.
In the 1980s, Kobilka, then newly recruited to work alongside Lefkowitz, was tasked with isolating the genetic code for one of the most pervasive of these cell receptors, the beta-adrenergic receptor. When they analysed the genetic blueprint, the team soon realised that there was a whole family of receptors that functioned in a similar way. These were named GPCRs.
Thanks to the pair's work, we now know that GPCRs represent one of the largest families of cell receptors. The pair also revealed how GPCRs are built, how they work and how they are regulated – incredibly important insights as these receptors are involved in almost all our physiological responses, including those involved in our sense of smell, immune system regulation and even changes in our mood.
GPCRs span the cell membrane and alert the inside of the cell to a change occurring outside, say an increase in a specific hormone. They do this not by letting the hormone through the membrane into the cell, but by changing shape when it attaches to a pocket on the outside of the receptor. This shape change allows molecules on the inside of the cell to attach themselves to the receptor, in turn triggering a cascade of metabolic changes within the cell.
In 2011, Kobilka's team was the first to capture an image of the beta-adrenergic receptor at the exact moment that it is activated by a hormone and sends a signal to the inside of the cell.
The pervasiveness of GPCRs means that half of the drugs we use today, for conditions ranging from gastric disorders to migraine and Parkinson's disease, rely on their action. Lefkowitz has also identified new families of proteins that desensitize GPCRs, helping us to understand how receptors become tolerant to some of these drugs.
Mark Sansom, head of biochemistry at the University of Oxford, says that GPCRs have been the holy grail of membrane protein research: "They are fundamental to regulation of many physiological processes. They are also a major class of drug target and are incredibly important to the pharmaceutical industry." He adds that Kobilka's work, in particular, "will lead to enormous advances in drug design."
"The practical benefits of Kobilka's and Lefkowitz's work highlight just how exciting and important chemistry is," says Martyn Poliakoff, vice-president of the Royal Society in London. "I hope that there are even more young people across the world who will be inspired to become chemists when they hear about the prize."
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