Open AccessUse of Backbone Modification To Enlarge the Spatiotemporal Diversity of Parathyroid Hormone Receptor-1 Signaling via Biased Agonism
Author(s) -
Shi Liu,
Frédéric JeanAlphonse,
Anna Marie White,
Denise Wootten,
Patrick M. Sexton,
Thomas J. Gardella,
Jean-Pierre Vilardaga,
Samuel H. Gellman
Publication year - 2019
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.9b04179
Subject(s) - chemistry , parathyroid hormone , parathyroid hormone receptor , receptor , hormone , g protein coupled receptor , endosome , microbiology and biotechnology , hormone receptor , signal transduction , medicine , endocrinology , biochemistry , calcium , biology , organic chemistry , cancer , breast cancer
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)-NH 2 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.