ArticlePloS one2014
Role of Ca2+ and L-Phe in regulating functional cooperativity of disease-associated "toggle" calcium-sensing receptor mutations.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 24 citations in OpenAlex.
- 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
- Molecular regulation of calcium-sensing receptor (CaSR)-mediated signaling.Chronic diseases and translational medicine · 2024Review
- Review
- Autosomal Dominant Hypocalcemia With Atypical Urine Findings Accompanied by NovelJournal of the Endocrine Society · 2021Article
- Structural Mechanism of Cooperative Regulation of Calcium-Sensing Receptor-Mediated Cellular Signaling.Current opinion in physiology · 2020Article
- Design of Calcium-Binding Proteins to Sense Calcium.Molecules (Basel, Switzerland) · 2020Review
- Evolution of Our Understanding of the Hyperparathyroid Syndromes: A Historical Perspective.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2019Review
- The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases.Nature reviews. Endocrinology · 2018Review
- The Different Facets of Extracellular Calcium Sensors: Old and New Concepts in Calcium-Sensing Receptor Signalling and Pharmacology.International journal of molecular sciences · 2018Review
- A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin-biased signaling.Science signaling · 2018Article
- Disorders of the calcium-sensing receptor and partner proteins: insights into the molecular basis of calcium homeostasis.Journal of molecular endocrinology · 2016Review
- Pathogenic role of calcium-sensing receptors in the development and progression of pulmonary hypertension.American journal of physiology. Lung cellular and molecular physiology · 2016Article
- Recent advances in understanding the extracellular calcium-sensing receptor.F1000Research · 2016Review
- Molecular Basis of the Extracellular Ligands Mediated Signaling by the Calcium Sensing Receptor.Frontiers in physiology · 2016Review
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
The Ca(2+)-sensing receptor (CaSR) regulates Ca(2+) homeostasis in the body by monitoring extracellular levels of Ca(2+) ([Ca(2+)]o) and amino acids. Mutations at the hinge region of the N-terminal Venus flytrap domain (VFTD) produce either receptor inactivation (L173P, P221Q) or activation (L173F, P221L) related to hypercalcemic or hypocalcemic disorders. In this paper, we report that both L173P and P221Q markedly impair the functional positive cooperativity of the CaSR as reflected by [Ca(2+)]o-induced [Ca(2+)]i oscillations, inositol-1-phosphate (IP1) accumulation and extracellular signal-regulated kinases (ERK1/2) activity. In contrast, L173F and P221L show enhanced responsiveness of these three functional readouts to [Ca(2+)]o. Further analysis of the dynamics of the VFTD mutants using computational simulation studies supports disruption in the correlated motions in the loss-of-function CaSR mutants, while these motions are enhanced in the gain-of-function mutants. Wild type (WT) CaSR was modulated by L-Phe in a heterotropic positive cooperative way, achieving an EC50 similar to those of the two activating mutations. The response of the inactivating P221Q mutant to [Ca(2+)]o was partially rescued by L-Phe, illustrating the capacity of the L-Phe binding site to enhance the positive homotropic cooperativity of CaSR. L-Phe had no effect on the other inactivating mutant. Moreover, our results carried out both in silico and in intact cells indicate that residue Leu(173), which is close to residues that are part of the L-Phe-binding pocket, exhibited impaired heterotropic cooperativity in the presence of L-Phe. Thus, Pro(221) and Leu(173) are important for the positive homo- and heterotropic cooperative regulation elicited by agonist binding.
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