Use of Backbone Modification To Enlarge the Spatiotemporal Diversity of Parathyroid Hormone Receptor-1 Signaling via Biased Agonism
- 9 September 2019
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 141 (37), 14486-14490
- https://doi.org/10.1021/jacs.9b04179
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.Keywords
Funding Information
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK111427, R01 DK116780)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30 AR066261)
- National Institute of General Medical Sciences (R01 GM056414)
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