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Arrestin Times for Developing Antipsychotics and {beta}-Blockers

Heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) are the largest group of structurally related proteins encoded by the human genome. As signal effectors and allosteric regulators, GPCRs dynamically recruit not only specific heterotrimeric G proteins but also the cytosolic scaffold proteins, β-arrestin 1 and 2, which were originally thought only to serve as negative regulators of GPCR signaling. Although about half of currently available therapeutics target GPCR function, usually at the ligand-binding, orthosteric site, evidence suggests that β-arrestins may be therapeutic targets themselves. Indeed, a hitherto undiscovered action of various antipsychotics is to inhibit the ability of the dopamine D2 receptor to engage β-arrestin 2 and activate glycogen synthase kinase 3, which may be a target for developing therapeutics for schizophrenia. Also, certain β-antagonists (blockers) used to treat heart failure, such as carvedilol, have the added effect of promoting activation of extracellular signal-regulated kinase through β-arrestin. It seems likely that the structure of β-arrestins allows them to detect different types and conformational states of GPCRs and to respond in functionally distinct fashions by using separate cohorts of signaling proteins, thus generating additional possibilities for therapeutic intervention.

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Resource Type: Bibliography, Diagram, Illustration, Journal article/Issue, Review
Audience Level: Undergraduate upper division 15-16, Graduate, Professional (degree program)

Author and Copyright

Authors and Editors: Miles D. Houslay of Faculty of Biomedical and Life Sciences, University of Glasgow
Publisher: American Association for the Advancement of Science
Format: application/pdf, image/gif, image/jpeg, text/html
Copyright and other restrictions: Yes
Cost: Yes


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