ArticleJournal of the American Society of Nephrology : JASN2015
Pathophysiologic Changes in Extracellular pH Modulate Parathyroid Calcium-Sensing Receptor Activity and Secretion via a Histidine-Independent Mechanism.
Article in Journal of the American Society of Nephrology : JASN, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 40 citations in OpenAlex.
- Acidic extracellular pH-induced PTH secretion in male mouse parathyroids is OGR1-dependent.Endocrinology · 2026Article
- Impact of Clinoptilolite and Anionic Salts on Calcium Homeostasis, Parathyroid Hormone, and Related Metabolic Parameters in Periparturient Dairy Cows.Veterinary sciences · 2026Article
- Associations between prepartum urine pH and periparturient blood calcium concentrations in multiparous Holstein cows.Frontiers in veterinary science · 2025Article
- The calcium-sensing receptor: a comprehensive review on its role in calcium homeostasis and therapeutic implications.American journal of translational research · 2025Review
- Metabolic acidosis in chronic kidney disease: mere consequence or also culprit?Pflugers Archiv : European journal of physiology · 2024Review
- The Role of the Endocrine System in the Regulation of Acid-Base Balance by the Kidney and the Progression of Chronic Kidney Disease.International journal of molecular sciences · 2024Review
- The Effects of Acid on Calcium and Phosphate Metabolism.International journal of molecular sciences · 2024Review
- Proton pump inhibitors display anti-tumour potential in glioma.Cell proliferation · 2023Review
- Temperature sensing by the calcium-sensing receptor.Frontiers in physiology · 2023Article
- Role of Calcimimetics in Treating Bone and Mineral Disorders Related to Chronic Kidney Disease.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Ion Channels, Transporters, and Sensors Interact with the Acidic Tumor Microenvironment to Modify Cancer Progression.Reviews of physiology, biochemistry and pharmacology · 2022Review
- Physiologic Regulation of Systemic Klotho Levels by Renal CaSR Signaling in Response to CaSR Ligands and pH o.Journal of the American Society of Nephrology : JASN · 2021Article
- Review
- Therapeutic Opportunities of Targeting Allosteric Binding Sites on the Calcium-Sensing Receptor.ACS pharmacology & translational science · 2021Review
- Structural Mechanism of Cooperative Regulation of Calcium-Sensing Receptor-Mediated Cellular Signaling.Current opinion in physiology · 2020Article
- International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function.Pharmacological reviews · 2020Review
- Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion.Nature communications · 2019Article
- Children and adolescents with cystic fibrosis display moderate bone microarchitecture abnormalities: data from high-resolution peripheral quantitative computed tomography.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2017Article
- Acid Load and Phosphorus Homeostasis in CKD.American journal of kidney diseases : the official journal of the National Kidney Foundation · 2017Article
- Deviations from the expected relationship between serum FGF23 and other markers in children with CKD: a cross-sectional study.BMC nephrology · 2017Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 3 countries.
Funding
Abstract
The calcium-sensing receptor (CaR) modulates renal calcium reabsorption and parathyroid hormone (PTH) secretion and is involved in the etiology of secondary hyperparathyroidism in CKD. Supraphysiologic changes in extracellular pH (pHo) modulate CaR responsiveness in HEK-293 (CaR-HEK) cells. Therefore, because acidosis and alkalosis are associated with altered PTH secretion in vivo, we examined whether pathophysiologic changes in pHo can significantly alter CaR responsiveness in both heterologous and endogenous expression systems and whether this affects PTH secretion. In both CaR-HEK and isolated bovine parathyroid cells, decreasing pHo from 7.4 to 7.2 rapidly inhibited CaR-induced intracellular calcium (Ca(2+)i) mobilization, whereas raising pHo to 7.6 potentiated responsiveness to extracellular calcium (Ca(2+)o). Similar pHo effects were observed for Ca(2+)o-induced extracellular signal-regulated kinase phosphorylation and actin polymerization and for L-Phe-induced Ca(2+)i mobilization. Intracellular pH was unaffected by acute 0.4-unit pHo changes, and the presence of physiologic albumin concentrations failed to attenuate the pHo-mediated effects. None of the individual point mutations created at histidine or cysteine residues in the extracellular domain of CaR attenuated pHo sensitivity. Finally, pathophysiologic pHo elevation reversibly suppressed PTH secretion from perifused human parathyroid cells, and acidosis transiently increased PTH secretion. Therefore, pathophysiologic pHo changes can modulate CaR responsiveness in HEK-293 and parathyroid cells independently of extracellular histidine residues. Specifically, pathophysiologic acidification inhibits CaR activity, thus permitting PTH secretion, whereas alkalinization potentiates CaR activity to suppress PTH secretion. These findings suggest that acid-base disturbances may affect the CaR-mediated control of parathyroid function and calcium metabolism in vivo.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.