ArticleHuman molecular genetics2018
Calcium-sensing receptor residues with loss- and gain-of-function mutations are located in regions of conformational change and cause signalling bias.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 28 citations in OpenAlex.
- Clinical and genetic insights into Autosomal Dominant Hypocalcemia type 1: a single-center case series including genotype-phenotype correlations, pregnancy outcomes, and novel CASR variants.Journal of endocrinological investigation · 2026Article
- A novel gain-of-function mutation (W818R) of calcium-sensing receptor in a family with autosomal dominant hypocalcemia type 1.Frontiers in endocrinology · 2026Article
- Calcium sensing receptor expression is downregulated in gastroenteropancreatic neuroendocrine tumours via epigenetic mechanisms.International journal of cancer · 2025Article
- An activating calcium-sensing receptor variant with biased signaling reveals a critical residue for Gα11 coupling.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2025Article
- Analysis of Calcium-Sensing Receptor Signaling Using Dual Luciferase Assays.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Review
- Identification of 4 New Loci Associated With Primary Hyperparathyroidism (PHPT) and a Polygenic Risk Score for PHPT.The Journal of clinical endocrinology and metabolism · 2022Article
- Genetics of monogenic disorders of calcium and bone metabolism.Clinical endocrinology · 2022Review
- The importance of kidney calcium handling in the homeostasis of extracellular fluid calcium.Pflugers Archiv : European journal of physiology · 2022Review
- Symmetric activation and modulation of the human calcium-sensing receptor.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- The role of calcium-sensing receptor signaling in regulating transepithelial calcium transport.Experimental biology and medicine (Maywood, N.J.) · 2021Review
- Heterogeneity of G protein activation by the calcium-sensing receptor.Journal of molecular endocrinology · 2021Article
- Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor.Science advances · 2021Article
- Calcium-sensing receptor signaling - How human disease informs biology.Current opinion in endocrine and metabolic research · 2021Article
- Biased signaling in naturally occurring mutations of G protein-coupled receptors associated with diverse human diseases.Biochimica et biophysica acta. Molecular basis of disease · 2021Review
- A Novel Germline c.1267T>AGenes · 2020Article
- Outcome of Clinical Genetic Testing in Patients with Features Suggestive for Hereditary Predisposition to PTH-Mediated Hypercalcemia.Hormones & cancer · 2020Article
- Genetics of kidney stone disease.Nature reviews. Urology · 2020Review
- Neonatal Hypocalcemic Seizures in Offspring of a Mother With Familial Hypocalciuric Hypercalcemia Type 1 (FHH1).The Journal of clinical endocrinology and metabolism · 2020Article
- Pancreatitis: TIGAR-O Version 2 Risk/Etiology Checklist With Topic Reviews, Updates, and Use Primers.Clinical and translational gastroenterology · 2019Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
The calcium-sensing receptor (CaSR) is a homodimeric G-protein-coupled receptor that signals via intracellular calcium (Ca2+i) mobilisation and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK) to regulate extracellular calcium (Ca2+e) homeostasis. The central importance of the CaSR in Ca2+e homeostasis has been demonstrated by the identification of loss- or gain-of-function CaSR mutations that lead to familial hypocalciuric hypercalcaemia (FHH) or autosomal dominant hypocalcaemia (ADH), respectively. However, the mechanisms determining whether the CaSR signals via Ca2+i or ERK have not been established, and we hypothesised that some CaSR residues, which are the site of both loss- and gain-of-function mutations, may act as molecular switches to direct signalling through these pathways. An analysis of CaSR mutations identified in >300 hypercalcaemic and hypocalcaemic probands revealed five 'disease-switch' residues (Gln27, Asn178, Ser657, Ser820 and Thr828) that are affected by FHH and ADH mutations. Functional expression studies using HEK293 cells showed disease-switch residue mutations to commonly display signalling bias. For example, two FHH-associated mutations (p.Asn178Asp and p.Ser820Ala) impaired Ca2+i signalling without altering ERK phosphorylation. In contrast, an ADH-associated p.Ser657Cys mutation uncoupled signalling by leading to increased Ca2+i mobilization while decreasing ERK phosphorylation. Structural analysis of these five CaSR disease-switch residues together with four reported disease-switch residues revealed these residues to be located at conformationally active regions of the CaSR such as the extracellular dimer interface and transmembrane domain. Thus, our findings indicate that disease-switch residues are located at sites critical for CaSR activation and play a role in mediating signalling bias.
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