Premium
A naturally occurring isoform inhibits parathyroid hormone receptor trafficking and signaling
Author(s) -
Alonso Verónica,
Ardura Juan A,
Wang Bin,
Sneddon W Bruce,
Friedman Peter A
Publication year - 2011
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.167
Subject(s) - parathyroid hormone , gene isoform , receptor , signal transduction , calcium sensing receptor , endocrinology , medicine , microbiology and biotechnology , biology , calcium , genetics , gene
Parathyroid hormone (PTH) regulates calcium homeostasis and bone remodeling through its cognitive receptor (PTHR). We describe here a PTHR isoform harboring an in‐frame 42‐bp deletion of exon 14 (Δe14‐PTHR) that encodes transmembrane domain 7. Δe14‐PTHR was detected in human kidney and buccal epithelial cells. We characterized its topology, cellular localization, and signaling, as well as its interactions with PTHR. The C‐terminus of the Δe14‐PTHR is extracellular, and cell surface expression is strikingly reduced compared with the PTHR. Δe14‐PTHR displayed impaired trafficking and accumulated in endoplasmic reticulum. Signaling and activation of cAMP and ERK by Δe14‐PTHR was decreased significantly compared with PTHR. Δe14‐PTHR acts as a functional dominant‐negative by suppressing the action of PTHR. Cells cotransfected with both receptors exhibit markedly reduced PTHR cell membrane expression, colocalization with Δe14‐PTHR in endoplasmic reticulum, and diminished cAMP activation and ERK phosphorylation in response to challenge with PTH. Δe14‐PTHR forms heterodimers with PTHR, which may account for cytoplasmic retention of PTHR in the presence of Δe14‐PTHR. Analysis of the PTHR heteronuclear RNA suggests that base‐pair complementarity in introns surrounding exon 14 causes exon skipping and accounts for generation of the Δe14‐PTHR isoform. Thus Δe14‐PTHR is a poorly functional receptor that acts as a dominant‐negative of PTHR trafficking and signaling and may contribute to PTH resistance. © 2011 American Society for Bone and Mineral Research.