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

Posted: October 11, 2012 in Events, Science

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.

  1. BrianJ says:

    Nice write-up, and you’re definitely right to highlight the importance of biased agonism. I have no idea how voters decide who gets a Nobel and who doesn’t when most work is so collaborative—and competitive—these days. I can certainly see someone(s) getting an award for biased agonism/functional selectivity. I’m not sure if it will include Lefkowitz, though. There are just so many working in the field, and he didn’t discover it. (I’m not sure who should take that credit, mind you.)

    There is one paragraph that is bugging me though… (Pedantry Alert!) Okay, maybe it isn’t totally pedantic, since part of what I’ll say is germane to biased agonism. A couple of points:

    1) Lock and key model: This is a really bad model. (I know you didn’t come up with it, so I’m not blaming you!) First, what effects the change in a lock’s confirmation? It is the force from the key; i.e., the key “makes” the lock change. Agonist, however, do not exert any kind of force.

    Second, a key fits into a lock equally well when the lock is open or closed. This is not the case for GPCRs. The inactive conformation of the receptor has very low affinity for the agonist. How then does the agonist ever bind? It’s because GPCRs are molten molecules, wiggling and jiggling about in the membrane, all the while taking on a whole array of different conformations. Sometimes those spontaneous conformations are the “active” state; i.e., a GPCR that could turn on a G-protein even in the absence of agonist. This phenomenon is responsible for the low constitutive activity of most GPCRs and it’s the reason that inverse agonists can exist (for a really good example, see Agrp/MC4R). So while GPCRs are dancing away and momentarily take on an “active” conformation, that’s when the agonist can bind—and bind tightly. Once the agonist is there, it stabilizes the active conformation of the receptor; i.e., it restricts the receptor’s movement to only a subset of dance moves. Antagonists, of course, opportunistically bind once the receptor wiggles into an “inactive” state. And so of course, the difference between two biased ligands is that they prefer different states of the receptor—and therefore promote the receptor staying in one state over the other.

    2) Agonist binding site: For Class A—aka rhodopsin-like—GPCRs (of which the beta-adrenergic receptors are members), the binding site for the agonist is within a pocket formed by the 7 transmembrane helices. While there is huge variability among receptors/ligands, the binding pocket can be deep inside the core of the receptor—as deep as within the lipid bilayer. On the other hand, Class C GPCRs, which include GABA receptors, have a humongous N-terminal region that forms their ligand binding domain.

    3) Pre-bound proteins on the GPCR tail: My memory is a bit fuzzy on this, but I do not believe that G proteins bind to the “inactive” GPCR. Two considerations: First, if they did pre-bind, then it should be easy to co-immunoprecipitate a GPCR with its cognate G proteins, right? But this is actually very difficult to do, and it’s part of the reason it took so freaking long to discover Gq/11-coupling. Second, if this were true, then antagonists would act as partial dominant-negatives toward other GPCRs because they would lock up some of the free G protein—the G protein would stay stuck to the antagonized GPCR. So I believe the correct model is that the GPCR and the heterotrimeric G protein are not pre-bound to one another.

    4) G protein binding site: Most GPCRs activate G proteins via their third intracellular loop. Some use the second intracellular loop. I know of none that use—or even need—their tail to activate G protein.

    Okay, end of rant. Again, sorry if that was not both helpful and interesting!

    • Hi Brian, thanks so much for your thoughtful and thorough comment. I definitely agree that the lock and key model is way outdated; I like your dance comparison though! Perhaps you could help come up with a better metaphor for how biased agonism works, maybe multiple dance partners for a specific receptor who each lead the receptor in a different dance etc. And yes, I agree with all of the other points you made regarding GPCR biology and signal transduction. That being said, I was aiming this article for consumption by the general public (aka not GPCR researchers), and thus decided to leave out much of the details. I worry that a non-science based person would stop reading past the first few sentences if the writing gets too complicated and full of detailed science info. Its definitely a struggle to write in a way to engage the general public but not scare them away or bore them to death (my blog is a work in progress towards that goal I guess). My main goal of the article was to get people excited about the possibilities of biased agonism and why GPCRs are so exciting. But again, thank you for your comment, now if people are interested, they can read even more about how GPCRs work (also why I posted a link to Lefkowitz’s latest review article)!

  2. BrianJ says:

    And I think you did a great job of pointing out the exciting possibilities still awaiting us in this field. Many people would see the headlines and think, “Okay, if a Nobel was awarded, then I guess we know what we need to know about GPCRs, right?” As you point out, we’ve only started—there’s at least “another Nobel’s worth” of information to discover. Unfortunately, the ratio of praise:criticism paragraphs in my comment don’t reflect that I really did like your article! 🙂

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