Study identifies potential new pathway for drug development

December 10, 2012

A newly found understanding of receptor signaling may have revealed a better way to design drugs. A study from Nationwide Children's Hospital suggests that a newly identified group of proteins, alpha arrestins, may play a role in cell signaling that is crucial to new drug development. The study appears in PLOS ONE.

More than one-third of drugs on the market work by targeting G protein-coupled receptors that control how cells communicate and function. With many hundreds of members, G protein-coupled receptors are the largest family of signaling receptors throughout the body.

Once a cell's G protein-coupled receptor binds with a natural ligand or a drug, intracellular G proteins and beta arrestins independently mediate various signals. Immediately following, beta arrestins block further signaling of and recruit proteins to remove the receptor to halt cell signaling. Those receptors can subsequently recycle to the cell surface or be destroyed.

"Receptor down regulation caused by beta arrestins can interfere with drug efficacy because the G protein-coupled receptor that the drug has been targeting is absent from the ," said Carlos E. Alvarez, PhD, principal investigator in the Center for Molecular and at The Research Institute at Nationwide Children's Hospital and lead study author. "This is why patients who are prescribed long-term medication can become drug-tolerant and require higher and higher doses."

In some cases, a drug's ability to trigger beta arrestin effects and block G protein signaling is preferential. Take beta blockers, for example. As the name suggests, beta blockers interfere with the binding to the receptor for epinephrine and other , weakening the hormones' effects and therefore being useful in treating irregular heartbeats, prevention of second heart attacks, hypertension and other conditions. Screening has revealed that the beta blocker may be the most ideal for treatment of as it reduces the cardiotoxic effects of G protein signaling, while increasing the cardioprotective effects of beta arrestin signaling.

Yet, it seems that beta arrestins may only be part of the cell signaling story. In 2008, Dr. Alvarez discovered a subfamily of arrestins that his team named alpha arrestins. In the current study, Fortune Shea in Dr. Alvarez's lab used biochemical and imaging approaches to further identify the role alpha arrestins play in .

He found that alpha arrestins respond to receptor binding and recruit enzymes that chemically modify the receptor to initiate aspects of down regulation. These effects occur in the first five minutes after the receptor is bound, the same time frame that beta arrestins are known to have roles in triggering down regulation. The team is also the first to find that alpha arrestins function coordinately with beta arrestins.

"Our findings suggest that alpha arrestins, like beta arrestins, are ubiquitous regulators of G-protein coupled receptor signaling," says Dr. Alvarez. "It seems that like beta arrestins, alpha arrestins could have great pharmacological relevance."

A major effort in pharmacology is to develop drugs with functional selectivity that either target G protein or beta arrestin signaling effects. Dr. Alvarez foresees alpha arrestins becoming a big player in the refining of such efforts.

"Just as has been discovered with and beta arrestin, I expect we'll find drugs that also have significant alpha arrestin effects," he says. "I believe that targeting alpha arrestins will allow us to develop compounds that are more effective and have reduced side effects," says Dr. Alvarez.

Explore further: Researchers learn how lung fibrosis begins and could be treated

More information: Shea F, Rowell J, Li Y, Chang TH, Alvarez C. Mammalian alpha arrestins link activated seven transmembrane receptors to Nedd4 family E3 ubiquitin ligases and interact with beta arrestins. PLOS ONE. www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0050557

Related Stories

Recommended for you

New 'Tissue Velcro' could help repair damaged hearts

August 28, 2015

Engineers at the University of Toronto just made assembling functional heart tissue as easy as fastening your shoes. The team has created a biocompatible scaffold that allows sheets of beating heart cells to snap together ...

Fertilization discovery: Do sperm wield tiny harpoons?

August 26, 2015

Could the sperm harpoon the egg to facilitate fertilization? That's the intriguing possibility raised by the University of Virginia School of Medicine's discovery that a protein within the head of the sperm forms spiky filaments, ...

Research identifies protein that regulates body clock

August 26, 2015

New research into circadian rhythms by researchers at the University of Toronto Mississauga shows that the GRK2 protein plays a major role in regulating the body's internal clock and points the way to remedies for jet lag ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.