GPCR Activation Activation's Illuminating Mechanisms

GPCR Activation Activation's Illuminating Mechanisms ...

Nearly a third of all drugs licensed by the Food and Drug Administration are in possession of a vast variety of biomolecules, known as G protein-coupled receptors (GPCRs) which can trigger cellular responses to extracellular stimuli. More than 800 different kinds of GPCRs exist in the human body and have a large effect on pathobiology and treatment of countless medical conditions, including cancer, type 2 diabetes, obesity, sleep disorders, and depression.

A multidisciplinary team of researchers has gained valuable insight into the way GPCRs operate, making an investment in improved therapies with less 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 head of molecular therapeutics at the New York State Psychiatric Institute.

Drugs that target GPCRs may be serious, but some of them are effective in treating pain. But they may also cause respiratory distress and constipation. At the moment, these compounds are incapable to target the pain-alleviating signaling pathway without also activating the respiratory and gut pathways.

We employ a method to investigate in unprecedented detail how drug-stimulated GPCRs activate -arrestin, a protein involved in both terminating some signals and mediating others, according toWesley B. Asher, PhD, the co-first author and assistant professor of clinical neurobiology in the Department of Psychiatry at Columbia, with the objective of enabling the development of pathway-specific compounds.

The study, published in the journalCell, involved the use of a cutting-edge technology called smFRET imaging, which is able to see structural changes of one protein in real time. This technique, developed by co-senior authorScott C. Blanchard, has captured movement within individual protein systems in unprecedented detail. It also allows insights that are obscured by other traditional approaches that average large quantities of proteins in a sample.

The scientists at smFRET decided to investigate the beta-adrenergic receptora prototypical GPCR that is widely applicable to many areas of biology. Binding of drugs or endogenous hormones to beta-adrenergic receptors or other GCPRs on the cell''s 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 may activate

Researchers investigated the process of -arrestin activation by a beta-adrenergic receptors, revealing further details about how -arrestins interact with, and are activated by GPCRs, processes that require the release of autoinhibition of both proteins.

The findings might, in turn, assist to identify improved medications that, by adjusting the binding and/or activation of -arrestin to GPCRs, can affect certain pathways, and not others.

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

Scientists believe that a better understanding of the relationship between receptor barcodes and -arrestin activation might further clarify the scope of specific downstream pathways, but not others.

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