TY  - JOUR
A1  - Klenk, Christoph
A1  - Hommers, Leif
A1  - Lohse, Martin J.
T1  - Proteolytic cleavage of the extracellular domain affects signaling of parathyroid hormone 1 receptor
JF  - Frontiers in Endocrinology
N2  - Parathyroid hormone 1 receptor (PTH1R) is a member of the class B family of G protein-coupled receptors, which are characterized by a large extracellular domain required for ligand binding. We have previously shown that the extracellular domain of PTH1R is subject to metalloproteinase cleavage in vivo that is regulated by ligand-induced receptor trafficking and leads to impaired stability of PTH1R. In this work, we localize the cleavage site in the first loop of the extracellular domain using amino-terminal protein sequencing of purified receptor and by mutagenesis studies. We further show, that a receptor mutant not susceptible to proteolytic cleavage exhibits reduced signaling to G\(_s\) and increased activation of G\(_q\) compared to wild-type PTH1R. These findings indicate that the extracellular domain modulates PTH1R signaling specificity, and that its cleavage affects receptor signaling.
KW  - GPCRs
KW  - parathyroid hormone 1 receptor
KW  - matrix metalloproteinase
KW  - ectodomain cleavage
KW  - biased signaling
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262055
SN  - 1664-2392
VL  - 13
ER  -