GPCR Activation's Illuminating Mechanisms

GPCR Activation's Illuminating Mechanisms ...

Nearly a third of all drugs approved by the Food and Drug Administration are aimed at a large broad spectrum of biomolecules, known as G protein-coupled receptors. These functions are to help with cellular responses 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 ailments, including cancer, type 2 diabetes, obesity, sleep disorders, and depression.

A multidisciplinary team of researchers has gained new insight into how GPCRs operate, paving the way toward improved drugs with fewer side effects.

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

Drugs that target GPCRs are usually known as opioid receptors, but they also have side effects, including respiratory distress and constipation. At the moment, these compounds are unable to modify the pain-alleviating signaling pathway without also activating the respiratory and gut pathways.

In our study, we employ a method that allows us to examine in unprecedented detail how drug-stimulated GPCRs activate -arrestin, a protein involved in removing some signals and directing others, according toWesley B. Asher, PhD, the co-first author and assistant professor of clinical neurobiology at the University of Colorado, with the objective of enabling the development of pathway-specific compounds.

The study, published in the journalCell, involved the use of a cutting-edge technique called "SmFRET," imaging. It includes the ability to see structural changes of single proteins in real time. This technique, developed by co-senior author Scott Blanchard, has enables insights that have been hampered by other traditional approaches.

The group, which was working with smFRET, decided to investigate the prototypical beta-adrenergic receptors on the cells'' exterior membrane. These reactions are mediated by the activation of G proteins. However, binding of another type of protein, -arrestins, terminates this signaling and can activate otherdesired or undesireddownstream pathways.

Researchers uncovered new details about how -arrestins interact with and are activated by GPCRs, processes that require the release of autoinhibition of both proteins.

These findings suggest that further investigation will be used to identify advanced drugs that, by modifying the binding and/or activation of -arrestin to GPCRs, have an impact on certain pathways and not others.

The results of the study have a barcode argument, which states that different phosphorylation patterns or barcodes within receptors may lead to different modes of -arrestin activation, which in turn dicts downstream signaling results.

Scientists hope that a better understanding of the relationship between receptor barcodes and -arrestin activation may entail significant insight into how specific downstream pathways, but not others, are aimed.

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