TY - JOUR
T1 - Use of Backbone Modification to Enlarge the Spatiotemporal Diversity of Parathyroid Hormone Receptor-1 Signaling via Biased Agonism
AU - Liu, Shi
AU - Jean-Alphonse, Frederic G.
AU - White, Alex D.
AU - Wootten, Denise
AU - Sexton, Patrick M.
AU - Gardella, Thomas J.
AU - Vilardaga, Jean Pierre
AU - Gellman, Samuel H.
PY - 2019/9/18
Y1 - 2019/9/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85072355553&partnerID=8YFLogxK
U2 - 10.1021/jacs.9b04179
DO - 10.1021/jacs.9b04179
M3 - Article
C2 - 31496241
AN - SCOPUS:85072355553
VL - 141
SP - 14486
EP - 14490
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
SN - 0002-7863
IS - 37
ER -