New Understanding of Receptor Regulation Suggests Target for New Drugs

A study leading to improved understanding of G-protein coupled receptor regulation suggests a new set of targets for designing drugs to more effectively regulate this medically important family of receptors.

More than one-third of drugs on the market directly or indirectly regulate G protein-coupled receptors (GPCRs). Some indirect drugs trigger beta arrestins that downregulate activated GPCRs mainly by causing the receptors to be removed from the cell surface to be subsequently recycled or, via ubiquitination, degraded. The natural action of beta arrestins lowers the cell surface concentration of GPCRs and so can interfere with drugs designed to directly target GPCRs, in some cases leading to drug tolerance in patients and a need for using higher doses.

The current study, led by principal investigator Carlos E. Alvarez, PhD, at Nationwide Children's Hospital (Columbus, OH, USA), identified related GPCR regulatory roles by another subfamily of arrestins, the “alpha arrestins,” recently discovered by Dr. Alvarez’s laboratory. Using biochemical and imaging approaches, the researchers now found that alpha arrestins respond to ligand-bound receptor activation, and recruit enzymes that chemically modify the receptor to initiate aspects of down-regulation. Time course studies showed that these effects occur in the first 1-5 minutes after ligand activation, the same time frame that beta arrestins are known to trigger receptor downregulation. Using coimmunoprecipitation and co-localization methods, the researchers were also the first to find strong evidence suggesting 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," said Dr. Alvarez. A major effort in current pharmacology is to develop drugs with functional selectivity that target either G protein or beta arrestin signaling effects. Dr. Alvarez foresees alpha arrestins becoming important in refining such efforts. "Just as has been discovered with beta blockers and beta arrestin, I expect we'll find drugs that also have significant alpha arrestin effects," said Dr. Alvarez.

The study was published online December 7, 2012, in the journal PLoS One.

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