Codes for the beta receptor: A Noble Performance: Civil Services Mentor Magazine December 2012

In our eyes, nose and mouth, we have sensors for light, odours and flavours. Within the body, cells have similar sensors for hormones and signalling substances, such as adrenalin, serotonin, histamine and dopamine. As life evolved, cells have repeatedly used the same basic mechanism for reading their environment: G-protein– coupled receptors. But they remained hidden from researchers for a long time. In a human, tens of thousands of billions of cells interact. Most of them have developed distinct roles. Some store fat; others register visual impressions, produce hormones or build up muscle tissue. In order for us to function, it is crucial that our cells work in unison, that they can sense their environment and know what is going on around them. For this, they need sensors. Sensors on the cell surface are called receptors. Robert J. Lefkowitz and Brian K. Kobilka are awarded the 2012 Nobel Prize in Chemistry for having mapped how a family of receptors called Gprotein– coupled receptors (GPCRs) work. In this family, we find receptors for adrenalin (also known as epinephrine), dopamine, serotonin, light, flavour and odour. Most physiological processes depend on GPCRs. Around half of all medications act through these receptors, among them beta blockers, antihistamines and various kinds of psychiatric medications. Knowledge about GPCRs is thus of the greatest benefit to mankind. However, these receptors eluded scientists for a long time.

AN ELUSIVE ENIGMA

At the end of the 19th Century, scientists began experimenting with adrenalin’s effects on the body. They soon realised that it does not work via nerves in the body and they concluded that cells must have some kind
of receptor that enables them to sense chemical substances — hormones, poisons and drugs — in their environment. But when researchers attempted to find these receptors, they hit a wall. They wanted to understand what the receptors look like and how they convey signals to the cell. The adrenalin was administered to the outside of the cell, and this led to changes in its metabolism that they could measure inside the cell. Each cell has a wall: a membrane of fat molecules that separates it from its environment. How did the signal get through the wall? How could the inside of the cell know what was happening on the outside? The receptors remained unidentified for decades. Despite this, scientists managed to develop drugs that specifically have their effect through one of these receptors. In the 1940s, the American scientist Raymond Ahlquist examined how different organs react to various adrenalin-like substances. His work led him to conclude that there must be two different types of receptors for adrenalin. He called the receptors alpha a n d beta. Such drugs undoubtedly produced effects in the cells, but how they did so remained a mystery. We now know  why the receptors were so difficult to find: they are relatively few in number and they also are mostly encapsulated within the wall of the cell. It was only at the end of the 1960s that Robert Lefkowitz enters the history of these receptors.

LURING RECEPTORS

The young top student has his mind set on becoming a cardiologist. However, he graduates at the height of the Vietnam War, and he does his military service in the US Public Health Service at a federal research institution, the National Institutes of Health. There he is presented with a grand challenge: finding the receptors. Lefkowitz’s supervisor already has a plan. He proposes attaching radioactive iodine to a hormone. Then, as the hormone binds to the surface of a cell, the radiation from the iodine should make it possible to track the receptor. Lefkowitz would also have to show that the hormone’s coupling to the cell’s outside actually triggers a process known to take place on the inside of the cell. Lefkowitz begins working with adrenocorticotropic hormone, which stimulates the production of adrenalin in the adrenal gland. As the project enters its second year, Lefkowitz finally makes some progress. In 1970, he publishes articles in two prestigious journals where he outlines the discovery of an active receptor. He is recruited to Duke University in North Carolina where he begins working on adrenalin and noradrenalin, so-called adrenergic receptors. Using radioactively tagged substances, including beta blockers, his research group examines how these receptors work. And after fine-tuning their toolkits, they manage with great skill to extract a series of receptors from biological tissue. Meanwhile, the knowledge about what happens inside cells has been growing. Researchers have found what they call G-proteins (Nobel Prize in Physiology or Medicine 1994) that are activated by a signal from the receptor. The G-protein, in turn, triggers a chain of reactions that alters the metabolism of the cell. By the beginning of the 1980s, scientists are starting to gain an understanding of the process by which signals are transmitted from the outside of the cell to its inside.