Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Cinacalcet corrects biased allosteric modulation of CaSR by AHH autoantibody
Noriko Makita, … , Masaomi Nangaku, Taroh Iiri
Noriko Makita, … , Masaomi Nangaku, Taroh Iiri
Published April 18, 2019
Citation Information: JCI Insight. 2019;4(8):e126449. https://doi.org/10.1172/jci.insight.126449.
View: Text | PDF
Research Article Endocrinology

Cinacalcet corrects biased allosteric modulation of CaSR by AHH autoantibody

  • Text
  • PDF
Abstract

Biased agonism is a paradigm that may explain the selective activation of a signaling pathway via a GPCR that activates multiple signals. The autoantibody-induced inactivation of the calcium-sensing receptor (CaSR) causes acquired hypocalciuric hypercalcemia (AHH). Here, we describe an instructive case of AHH in which severe hypercalcemia was accompanied by an increased CaSR antibody titer. These autoantibodies operated as biased allosteric modulators of CaSR by targeting its Venus flytrap domain near the Ca2+-binding site. A positive allosteric modulator of CaSR, cinacalcet, which targets its transmembrane domain, overcame this autoantibody effect and successfully corrected the hypercalcemia in this patient. Hence, this is the first study to our knowledge that identifies the interaction site of a disease-causing GPCR autoantibody working as its biased allosteric modulator and demonstrates that cinacalcet can correct the AHH autoantibody effects both in vitro and in our AHH patient. Our observations provide potentially new insights into how biased agonism works and how to design a biased allosteric modulator of a GPCR. Our observations also indicate that the diagnosis of AHH is important because the severity of hypercalcemia may become fatal if the autoantibody titer increases. Calcimimetics may serve as good treatment options for some patients with severe AHH.

Authors

Noriko Makita, Takao Ando, Junichiro Sato, Katsunori Manaka, Koji Mitani, Yasuko Kikuchi, Takayoshi Niwa, Masanori Ootaki, Yuko Takeba, Naoki Matsumoto, Atsushi Kawakami, Toshihisa Ogawa, Masaomi Nangaku, Taroh Iiri

×

Figure 1

Temporal profile of serum Ca levels in our AHH patient and identification of CaSR autoantibody.

Options: View larger image (or click on image) Download as PowerPoint
Temporal profile of serum Ca levels in our AHH patient and identificatio...
(A) Left: The corrected calcium levels in our patient’s serum over time. Shortly after the episode of spontaneous exacerbation of hypercalcemia, treatment with cinacalcet was started. Right: CaSR antibody activities before (arrows I and II) and after (arrow III) the treatment. Values represent mean ± SEM of triplicate determinations. Each set of results is representative of at least 2 additional experiments. Statistical analysis was performed using 2-way ANOVA with Dunnett’s test. ***P < 0.0001. (B) Left: Immunoperoxidase staining of HEK293 cells expressing human CaSR incubated with the AHH patient/control sera (1:50). Right: Colocalization (merge: yellow) of the AHH patient autoantibody (green) with monoclonal anti-CaSR (amino acids 15–29) antibody (red) was observed. Scale bar: 50 μm.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts