GPCR Activation's Illuminating Mechanisms

GPCR Activation's Illuminating Mechanisms ...

Nearly a third of all drugs approved by the Food and Drug Administration are in the pipeline of large biomolecules, known as G protein-coupled receptors, and have a mandate to facilitate cell response to extracellular stimuli. More than 800 different types of GPCRs exist in the human body and play a role in the pathobiology and treatment of countless medical illnesses, including cancer, type 2 diabetes, obesity, sleep disorders, and depression.

A diverse group of researchers has acquired new insight into how GPCRs work, making a difference in the development of improved drugs with less side effects.

GPCRs are widely used in medicineheart disease, lung disease, sleep and neuropsychiatric disorders, according to senior authorJonathan Javitch, MD, PhD, the Lieber Professor of Experimental Therapeutics at the Columbia University Vagelos College of Physicians and Surgeons, and the head of molecular therapeutics at the New York State Psychiatric Institute.

Some drugs that target GPCRs have side effects, including one that can be serious. For example, opioid receptors are effective in treating pain, but they also have side effects such as respiratory distress and constipation. At the moment, these compounds are unable to simultaneously activate the respiratory and gut pathways.

We employ a method to examine in unprecedented detail how drug-stimulated GPCRs activate -arrestin, a protein involved in halting certain signals and expressing others, according to Wesley B. Asher, PhD, a co-first author and assistant professor of clinical neurobiology at the University of Columbia, with the objective of enabling the development of pathway-specific compounds.

The study, published on April 27, involved the use of a cutting-edge technique called smFRET imaging. It is based on the knowledge of structural changes of individual proteins in unprecedented detail. It also assists in discovering patterns that differ from traditional approaches that average large quantities of proteins in a sample.

The researchers from smFRET decided to investigate the beta-adrenergic receptora prototypical GPCR that is broadly applicable to many different disciplines of biology. Binding of drugs or endogenous hormones to beta-adrenergic receptors on the cells'' exterior membrane leads to signals on the inside of the cell that are mediated by activation of G proteins. However, binding of another type of protein, -arrestins, terminates this signaling and can activate otherdesired or unde

The researchers explored the process of -arrestin activation by a beta-adrenergic receptors, and how -arrestins interact with and are activated by GPCRs, processes that require the release of both proteins.

These findings might hopefully help to identify improved drugs that, by modulating the binding and/or activation of -arrestin to GPCRs, may affect specific pathways and not others.

The results of the study support the barcode hypothesis, which states that different phosphorylation patterns or barcodes within receptors can lead to different levels of -arrestin activation, which in turn determines downstream signaling outcomes.

Scientists believe that a better understanding of the relationship between receptor barcodes and -arrestin activation may give an important insight into the direction that specific downstream pathways, but not others, are being targeted.

You may also like: