Intracellular Ca2+ oscillations generated via the extracellular Ca2+-sensing receptor (CaSR) in response to extracellular Ca2+ or l-phenylalanine: Impact of the highly conservative mutation Ser170Thr
The extracellular Ca2+-sensing receptor (CaSR) is an allosteric protein that responds to changes in the extracellular concentration of Ca2+ ([Ca2+]e) and aromatic amino acids with the production of different patterns of oscillations in intracellular Ca2+ concentration ([Ca2+]i). An increase in [Ca2+...
| Autores: | , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2015 |
| País: | Argentina |
| Institución: | Consejo Nacional de Investigaciones Científicas y Técnicas |
| Repositorio: | CONICET Digital (CONICET) |
| Idioma: | inglés |
| OAI Identifier: | oai:ri.conicet.gov.ar:11336/94909 |
| Acceso en línea: | http://hdl.handle.net/11336/94909 |
| Access Level: | acceso abierto |
| Palabra clave: | Calcium sensing receptor GPCR Calcium oscillations signal transduction https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
| Sumario: | The extracellular Ca2+-sensing receptor (CaSR) is an allosteric protein that responds to changes in the extracellular concentration of Ca2+ ([Ca2+]e) and aromatic amino acids with the production of different patterns of oscillations in intracellular Ca2+ concentration ([Ca2+]i). An increase in [Ca2+]e stimulates sinusoidal oscillations in [Ca2+]i whereas aromatic amino acid-induced CaR activation in the presence of a threshold [Ca2+]e promotes transient oscillations in [Ca2+]i. Here, we examined spontaneous and ligand-evoked [Ca2+]i oscillations in single HEK-293 cells transfected with the wild type CaSR or with a mutant CaSR in which Ser170 was converted to Thr (CaSRS170T). Our analysis demonstrates that cells expressing CaSRS170T display [Ca2+]i oscillations in the presence of low concentrations of extracellular Ca2+ and respond to L-Phe with robust transient [Ca2+]i oscillations. Our results indicate that the S170T mutation induces a marked increase in CaSR sensitivity to [Ca2+]e and imply that the allosteric regulation of the CaSR by aromatic amino acids is not only mediated by an heterotropic positive effect on Ca2+ binding cooperativity but, as biased agonists, aromatic amino acids stabilize a CaSR conformation that couples to a different signaling pathway leading to transient [Ca2+]i oscillations. |
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