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, beta-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 beta-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 beta-arrestin 2 and activate glycogen synthase kinase 3, which may be a target for developing therapeutics for schizophrenia. Also, certain beta-antagonists (blockers) used to treat heart failure, such as carvedilol, have the added effect of promoting activation of extracellular signal-regulated kinase through beta-arrestin. It seems likely that the structure of beta-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.
Neuroscience and Molecular Pharmacology, Wolfson and Davidson Buildings, University of Glasgow, Glasgow G12 8QQ, Scotland, UK. m.houslay@bio.gla.ac.uk
Miles D
MD
Houslay
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019393:Arrestin / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D000319:Adrenergic beta-Antagonists; D014150:Antipsychotic Agents; D019393:Arrestin; D043562:Receptors, G-Protein-Coupled