Thyrotropin-releasing hormone binding to the mouse pituitary receptor does not involve ionic interactions: A model for neutral peptide binding to G protein-coupled receptors

Jeffrey H. Perlman, Daniel R. Nussenzveig, Roman Osman, Marvin C. Gershengorn

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Abstract

Thyrotropin-releasing hormone, TRH (<Glu-His-Proamide), and [Nτ-Me-His]TRH (MeTRH) are present as neutral and positively charged forms at physiologic pH, and it was possible that they bind to the TRH receptor (TRH-R) as charged (protonated) species. Binding affinities of TRH and MeTRH to endogenous rat TRH-Rs and to transfected wild type mouse TRH-Rs decreased below pH 7.1. Half-maximal decreases in binding occurred at the approximate pKa values of these ligands. Asp to Ala mutations in extracellular loop 1, TM-4, and TM-5 did not decrease binding affinity, but an Asp to Ala mutation in TM-2 caused the affinity to decrease 8-fold. The pH dependences of binding of MeTRH, however, were similar in wild type and all mutant receptors and were consistent with the protonated form of MeTRH binding less well. Thus, the binding of TRH to its receptor does not involve ionic interactions and may be a prototype for binding of neutral peptide ligands to G protein-coupled receptors.

Original languageEnglish (US)
Pages (from-to)24413-24417
Number of pages5
JournalJournal of Biological Chemistry
Volume267
Issue number34
Publication statusPublished - Dec 5 1992

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ASJC Scopus subject areas

  • Biochemistry

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