ArticleJCI insight2019
Cinacalcet corrects biased allosteric modulation of CaSR by AHH autoantibody.
Article in JCI insight, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 16 citations in OpenAlex.
- Fibrosis suppressive effect and mechanism of CaSR positive allosteric modulators/p-dioxanone copolymers.Drug delivery and translational research · 2026Article
- Biased antibodies and beyond: a new era in the diagnosis of PTH-dependent hypercalcemia.Endocrine journal · 2025Review
- Insights into GLP-1 and insulin secretion mechanisms in pasireotide-induced hyperglycemia highlight effectiveness of Gs-targeting diabetes treatment.Scientific reports · 2025Article
- Autoimmune Autonomic Neuropathy: From Pathogenesis to Diagnosis.International journal of molecular sciences · 2024Review
- Revitalizing Skin Repair: Unveiling the Healing Power of Livisin, a Natural Peptide Calcium Mimetic.Toxins · 2023Article
- Successful prednisolone or calcimimetic treatment of acquired hypocalciuric hypercalcemia caused by biased allosteric CaSR autoantibodies.JCI insight · 2022Article
- Autoantibodies as Endogenous Modulators of GPCR Signaling.Trends in pharmacological sciences · 2021Review
- Calcium-sensing receptor signaling - How human disease informs biology.Current opinion in endocrine and metabolic research · 2021Article
- Illuminating the allosteric modulation of the calcium-sensing receptor.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function.Pharmacological reviews · 2020Review
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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