Calcium-Sensing Receptor Mechanisms in Endocrine Signaling

The calcium-sensing receptor (CaSR) is a class C G-protein-coupled receptor that serves as a central regulator of extracellular calcium homeostasis by modulating parathyroid hormone (PTH) secretion and renal calcium excretion. Beyond the parathyroid gland and kidney, CaSR is widely expressed in tissues such as pancreatic islets, intestinal epithelium and bone, where it integrates diverse chemical cues—including divalent cations and amino acids—to coordinate cellular function. Binding of extracellular Ca2+ or co-agonists to the receptor’s venus flytrap domain induces conformational changes that recruit G proteins (notably Gq and Gi/o), triggering intracellular signalling cascades such as phospholipase C activation, intracellular calcium mobilisation and MAP kinase phosphorylation. Through these pathways, CaSR influences hormone release, cell proliferation and ion transport. Dysregulation of CaSR underlies familial hypo- and hypercalcaemic disorders, contributes to tumour metastasis in calcium-rich microenvironments, and has been linked to cytokine-mediated hypocalcaemia in critical illness. Pharmacological modulators—calcimimetics and calcilytics—exploit allosteric sites to fine-tune receptor sensitivity, offering targeted therapies for conditions such as primary hyperparathyroidism, autosomal dominant hypocalcaemia and secretory diarrhoea. Emerging data reveal a nutrient-sensing role for the receptor in pancreatic α-cell mass regulation and identify magnesium as an endogenous activator in the gut, underscoring the global significance of CaSR in physiology and disease management.

Research from Nature Portfolio

Recent studies have demonstrated that under conditions of elevated amino acid levels pancreatic α-cell proliferation depends on CaSR activation through Gq-mediated ERK1/2 signalling. In murine islets and zebrafish models lacking glucagon receptor signalling, disruption of CaSR abolished adaptive α-cell expansion, a defect rescued by re-expression of CaSR or selective Gq activation. Unexpectedly, CaSR was also required for mTORC1 activation in α-cells, and combined stimulation of Gq and mTORC1 proved sufficient to drive proliferation independent of amino acid overload. These findings reveal a dual nutrient-sensing function for CaSR in islet plasticity and endocrine adaptation.

Calcium-Sensing Receptor Mechanisms in Endocrine Signaling publication trend

The graph below shows the total number of articles in calcium-sensing receptor mechanisms in endocrine signaling across all publications each year (not limited to Nature Index journals).

Technical terms

Calcium-sensing receptor (CaSR): A class C G-protein-coupled receptor that detects extracellular calcium and other ligands to regulate hormone secretion and ion transport.

Gq signalling: A pathway in which receptor-mediated activation of the Gq protein stimulates phospholipase C, leading to inositol trisphosphate generation and intracellular calcium release.

mTORC1: Mammalian target of rapamycin complex 1, a kinase complex that senses nutrients and controls cell growth, proliferation and metabolism.

Allosteric modulator: A compound that binds to a site distinct from the orthosteric ligand pocket on a receptor, altering its conformation and functional response.

References

1. Hyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways. Nature Communications (2023).
2. Mg2+ supplementation treats secretory diarrhea in mice by activating calcium-sensing receptor in intestinal epithelial cells. Journal of Clinical Investigation (2024).
3. Disorders of the calcium-sensing receptor and partner proteins: insights into the molecular basis of calcium homeostasis. Journal of Molecular Endocrinology (2016).
4. Structural basis for regulation of human calcium-sensing receptor by magnesium ions and an unexpected tryptophan derivative co-agonist. Science Advances (2016).
5. High calcium concentration in bones promotes bone metastasis in renal cell carcinomas expressing calcium-sensing receptor. Molecular Cancer (2014).
6. The Proinflammatory Cytokine, Interleukin-6, Up-regulates Calcium-sensing Receptor Gene Transcription via Stat1/3 and Sp1/3*. Journal of Biological Chemistry (2008).
7. Molecular Cloning and Functional Expression of Human Parathyroid Calcium Receptor cDNAs (∗). Journal of Biological Chemistry (1995).
8. The Calcilytic Agent NPS 2143 Rectifies Hypocalcemia in a Mouse Model With an Activating Calcium-Sensing Receptor (CaSR) Mutation: Relevance to Autosomal Dominant Hypocalcemia Type 1 (ADH1). Endocrinology (2015).