Use of Backbone Modification to Enlarge the Spatiotemporal Diversity of Parathyroid Hormone Receptor-1 Signaling via Biased Agonism

Shi Liu, Frederic G. Jean-Alphonse, Alex D. White, Denise Wootten, Patrick M. Sexton, Thomas J. Gardella, Jean Pierre Vilardaga, Samuel H. Gellman

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Abstract

The type-1 parathyroid hormone receptor (PTHR1), which regulates calcium homeostasis and tissue development, has two native agonists, parathyroid hormone (PTH) and PTH-related protein (PTHrP). PTH forms a complex with the PTHR1 that is rapidly internalized and induces prolonged cAMP production from endosomes. In contrast, PTHrP induces only transient cAMP production, which primarily arises from receptors on the cell surface. We show that backbone modification of PTH(1-34)-NH2 and abaloparatide (a PTHrP derivative) with a single homologous β-amino acid residue can generate biased agonists that induce prolonged cAMP production from receptors at the cell surface. This unique spatiotemporal profile could be useful for distinguishing effects associated with the duration of cAMP production from effects associated with the site of cAMP production.

Original languageEnglish
Pages (from-to)14486-14490
Number of pages5
JournalJournal of the American Chemical Society
Volume141
Issue number37
DOIs
Publication statusPublished - 18 Sep 2019

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