Why this may not be Dr. Lefkowitz's last Nobel Prize

Scientist Robert Lefkowitz, along with his former student Brian Kobilka, was awarded the 2012 Nobel Prize in Chemistry on Wednesday. His research pertaining to a family of receptors called G-Protein Coupled Receptors (GPCRs) lead to the award, but current work in Dr. Lefkowitz’s lab has the potential to change the way we think about medication even further.

Dr. Lefkowitz graduated from Columbia University with an M.D. degree in 1966. He is currently the James B. Duke Professor of Medicine at Duke University and has been a Howard Hughes Medical Investigator since 1976. In the 1980s, Dr. Lefkowitz’s laboratory was a major contributor to the cloning of several GPCRs, and this research lead to the discovery that all GPCRs have similar structure.

There are upwards of 800 known GPCRs in the human body, the largest family of receptors to date. GPCRs are proteins that loop back and forth across the membrane of a cell seven times. One tail of the receptor sticks out into the outside of the cell (extracellular space) and the other tail of the receptor is located inside of the cell (intracellular space). A multitude of chemical signals, such as hormones, taste molecules, and neurotransmitters, bind to and activate these types of receptors. These receptors are located throughout the body, from the brain to the heart to the reproductive organs. Importantly, about half of currently approved medications target these receptors, thus understanding how they work is crucial to future drug development.

With the help of Dr. Lefkowitz, we now understand that GPCRs and the molecules that bind them act as a sort of lock (GPCR) and key (molecule). When a molecule binds to the extracellular tail of a GPCR in the correct way (ie the key fits the lock), the GPCR will change shape in a way that affects the proteins that are already bound to the intracellular tail of the GPCR. The proteins bound to the intracellular tail are called G-proteins (hence the name G-Protein Coupled Receptor), and can become activated in response to the change in shape of the GPCR. Activated G-proteins can then un-attach from the intracellular tail and go on to activate additional downstream intracellular proteins, leading to a cascade of events inside the cell.

In addition to his work in the early 1980s on understanding how GPCRs work, Lefkowitz’s laboratory has also been seminal in the discovery that other proteins, besides the G-proteins, can interact with GPCRs and lead to downstream effects. The two main types of these proteins are G-protein coupled receptor kinases and beta-arrestins. There proteins were originally thought to regulate the trafficking and silencing of GPCRs, but more recently it has become appreciated that they can also act as signaling molecules themselves, similar to the actions of the activated G-proteins. Thus, when a molecule binds to a GPCR, it can activate multiple pathways (via the G-proteins and also via arrestin), or it can activate just a subset of pathways.

This type of signaling is now known as ‘ligand directed signaling’ or ‘biased agonism.’ In this type of signaling, the unbiased ligand (molecular key), usually the natural receptor ligand, activates multiple pathways via G-proteins and also via arrestins.  A biased ligand would then be a molecule that directs the signaling pathway in a specific direction via the activation of either the G-protein or the arrestin. Ligand directed signaling has gained appreciation for it’s potential to reduce the unwanted side effects of prescription drugs. Imagine you have a drug like morphine that produces pain relief but also has the unwanted side effects of tolerance and later dependence and subsequent addiction liability. Morphine works in the body by activating the mu opioid receptor (MOR), a GPCR. Now imagine that following MOR activation, one downstream pathway controls the pain relief and one pathway controls the tolerance and addiction liability. The potential to design a drug that activates just the pain relief pathway of the MOR receptor has huge implications for medicine.

Currently, many patients take prescription drugs to block or decrease the unwanted side effects of other prescription drugs. These drugs used to block side effects of other drugs may also have unwanted side effect, and on and on and on. This circular problem increases the number of prescriptions and the cost for patients around the world. There in lies the power of ligand directed signaling. If researchers can understand how to target only specific effects of receptor activation they can then better treat patients and decrease or even eliminate these unwanted side effects. Imagine a world where a patient can be treated for chronic pain without the risk of addiction to that pain medication.

Dr. Lefkowitz is only one of a multitude of researchers working on understanding ligand directed signaling, and only six Nobel laureates have received more than one prize, but with the multitude of posts and news articles discussing mainly his early work, I think it would be remiss not to discuss the groundbreaking work Lefkowitz and his team is currently conducting.

Go here for the Nobel Prize in Chemistry 2012 Information for the Public sheet. The information sheet contains a great write-up of the early work conducted by Dr. Lefkowitz and Dr. Kobilka.

Go here  for Dr. Lefkowitz’s most recent review regarding ligand directed signaling (warning, subscription required).

Go here for a recent scientific publication investigating ligand directed signaling at the mu opioid receptor.


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