Arrestin binds to different phosphorylated regions of the thyrotropin-releasing hormone receptor with distinct functional consequences.

Molecular Pharmacology
Brian W Jones, Patricia M Hinkle

Abstract

Arrestin binding to agonist-occupied phosphorylated G protein-coupled receptors typically increases the affinity of agonist binding, increases resistance of receptor-bound agonist to removal with high acid/salt buffer, and leads to receptor desensitization and internalization. We tested whether thyrotropin-releasing hormone (TRH) receptors lacking phosphosites in the C-terminal tail could form stable and functional complexes with arrestin. Fibroblasts from mice lacking arrestins 2 and 3 were used to distinguish between arrestin-dependent and -independent effects. Arrestin did not promote internalization or desensitization of a receptor that had key Ser/Thr phosphosites mutated to Ala (4Ala receptor). Nevertheless, arrestin greatly increased acid/salt resistance and the affinity of 4Ala receptor for TRH. Truncation of 4Ala receptor just distal to the key phosphosites (4AlaStop receptor) abolished arrestin-dependent acid/salt resistance but not the effect of arrestin on agonist affinity. Arrestin formed stable complexes with activated wild-type and 4Ala receptors but not with 4AlaStop receptor, as measured by translocation of arrestin-green fluorescent protein to the plasma membrane or chemical cross-linking. An arrestin mutant t...Continue Reading

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Citations

Jun 12, 2010·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Susanne NeumannMarvin C Gershengorn
May 18, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Alisa BoutinMarvin C Gershengorn
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Jun 18, 2011·Trends in Pharmacological Sciences·Sudha K Shenoy, Robert J Lefkowitz
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Mar 23, 2017·Journal of Cardiovascular Pharmacology·Pierre-Yves Jean-CharlesSudha K Shenoy
May 13, 2020·Proceedings of the National Academy of Sciences of the United States of America·Ivone GomesLakshmi A Devi

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