A Naturally Occurring Isoform Inhibits Parathyroid Hormone Receptor Trafficking and Signaling

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 (Delta e14-PTHR) that encodes transnnembrane domain 7. Delta e14-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 Delta e14-PTHR is extracellular, and cell surface expression is strikingly reduced compared with the PTHR. Delta e14-PTHR displayed impaired trafficking and accumulated in endoplasmic reticulum. Signaling and activation of cAMP and ERK by Delta e14-PTHR was decreased significantly compared with PTHR. Delta e14-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 Delta e14-PTHR in endoplasmic reticulum, and diminished cAMP activation and ERK phosphorylation in response to challenge with PTH. Delta e14-PTHR forms heterodimers with PTHR, which may account for cytoplasmic retention of PTHR in the presence of Delta e14-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 Delta e14-PTHR isoform. Thus Delta e14-PTHR is a poorly functional receptor that acts as a dominant-negative of PTHR trafficking and signaling and may contribute to PTH resistance. (C) 2011 American Society for Bone and Mineral Research.