GPCR Activation's Illuminating Mechanisms

GPCR Activation's Illuminating Mechanisms ...

About a third of all medicines approved by the Food and Drug Administration are people with biomolecules, known as G protein-coupled receptors (GPCRs), which are able to activate cell responses to extracellular stimuli. More than 800 different kinds of GPCRs exist in the human body and play a major role in the pathobiology and treatment of countless medical conditions, including cancer, type 2 diabetes, obesity, sleep disorders, schizophrenia, and depression.

A multidisciplinary team of researchers has now gained new insight into the way GPCRs operate, making an impact on improved drugs with less side effects.

GPCRs are used to treat a wide spectrum of maladies including 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.

Unlike many therapeutics, drugs that target GPCRs often have side effects, some of which may be serious. For example, drugs that target a group of GPCRs called opioid receptors are extremely effective in treating pain, but also have side effects such as respiratory distress and constipation. At the moment, these compounds are incapable of also activating the respiratory and gut pathways.

We use a method to analyze in unprecedented detail how drug-stimulated GPCRs activate -arrestin, a protein involved in terminating certain signals and in mediating others, according to Wesley B. Asher, PhD, the co-first author and assistant professor of clinical neurobiology at 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 the single-molecule fluorescence resonance energy transfer (SmFRET) imaging. The technique, developed by co-senior authorScott Blanchard, was used in the St. Jude Childrens Research Hospital, to visualize structural changes of single proteins in unprecedented detail. It also facilitates insights that are obscured by other traditional approaches that average large quantities of proteins in a sample.

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

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

The findings might ultimately help to identify better drugs that, by regulating the binding and/or activation of -arrestin to GPCRs, may influence specific pathways rather than others.

The findings suggest that different phosphorylation patterns or barcodes within receptors may lead to different patterns 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 permissive insight into the way specific downstream pathways, but not others, are targeted.

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