期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 141, 期 37, 页码 14486-14490出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.9b04179
关键词
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资金
- NIH [R0I GM056414, R0I DK111427, R0I DK116780, T32-GM008424, P01 DK11794, P30 AR066261]
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 beta-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.
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