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Cited 34 time in webofscience Cited 39 time in scopus
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Ca2+ allostery in PTH-receptor signaling

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dc.contributor.authorWhite, Alex D.-
dc.contributor.authorFang, Fei-
dc.contributor.authorJean-Alphonse, Frederic G.-
dc.contributor.authorClark, Lisa J.-
dc.contributor.authorAn, Hyun-Jung-
dc.contributor.authorLiu, Hongda-
dc.contributor.authorZhao, Yang-
dc.contributor.authorReynolds, Shelley L.-
dc.contributor.authorLee, Sihoon-
dc.contributor.authorXiao, Kunhong-
dc.contributor.authorSutkeviciute, Ieva-
dc.contributor.authorVilardaga, Jean-Pierre-
dc.date.available2020-02-27T04:41:29Z-
dc.date.created2020-02-05-
dc.date.issued2019-02-19-
dc.identifier.issn0027-8424-
dc.identifier.urihttps://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/1835-
dc.description.abstractThe parathyroid hormone (PTH) and its related peptide (PTHrP) activate PTH receptor (PTHR) signaling, but only the PTH sustains GS-mediated adenosine 3',5'-cyclic monophosphate (cAMP) production after PTHR internalization into early endosomes. The mechanism of this unexpected behavior for a G-protein-coupled receptor is not fully understood. Here, we show that extracellular Ca2+ acts as a positive allosteric modulator of PTHR signaling that regulates sustained cAMP production. Equilibrium and kinetic studies of ligand-binding and receptor activation reveal that Ca2+ prolongs the residence time of ligands on the receptor, thus, increasing both the duration of the receptor activation and the cAMP signaling. We further find that Ca2+ allostery in the PTHR is strongly affected by the point mutation recently identified in the PTH (PTHR25C) as a new cause of hypocalcemia in humans. Using high-resolution and mass accuracy mass spectrometry approaches, we identified acidic clusters in the receptor's first extracellular loop as key determinants for Ca2+ allosterism and endosomal cAMP signaling. These findings coupled to defective Ca2+ allostery and cAMP signaling in the PTHR by hypocalcemia-causing PTHR25C suggest that Ca2+ allostery in PTHR signaling may be involved in primary signaling processes regulating calcium homeostasis.-
dc.language영어-
dc.language.isoen-
dc.publisherNATL ACAD SCIENCES-
dc.relation.isPartOfPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-
dc.subjectPROTEIN-COUPLED RECEPTORS-
dc.subjectPARATHYROID-HORMONE-
dc.subjectAGONIST BINDING-
dc.subjectCAMP-
dc.subjectMG2+-
dc.subjectGENERATION-
dc.subjectRETROMER-
dc.titleCa2+ allostery in PTH-receptor signaling-
dc.typeArticle-
dc.type.rimsART-
dc.description.journalClass1-
dc.identifier.wosid000459074400074-
dc.identifier.doi10.1073/pnas.1814670116-
dc.identifier.bibliographicCitationPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.116, no.8, pp.3294 - 3299-
dc.identifier.scopusid2-s2.0-85061873534-
dc.citation.endPage3299-
dc.citation.startPage3294-
dc.citation.titlePROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-
dc.citation.volume116-
dc.citation.number8-
dc.contributor.affiliatedAuthorAn, Hyun-Jung-
dc.contributor.affiliatedAuthorLee, Sihoon-
dc.type.docTypeArticle-
dc.subject.keywordAuthorPTH-
dc.subject.keywordAuthorPTH receptor-
dc.subject.keywordAuthorGPCR signaling-
dc.subject.keywordAuthorCa2+ allosterism-
dc.subject.keywordAuthorendosomal cAMP signaling-
dc.subject.keywordPlusPROTEIN-COUPLED RECEPTORS-
dc.subject.keywordPlusPARATHYROID-HORMONE-
dc.subject.keywordPlusAGONIST BINDING-
dc.subject.keywordPlusCAMP-
dc.subject.keywordPlusMG2+-
dc.subject.keywordPlusGENERATION-
dc.subject.keywordPlusRETROMER-
dc.relation.journalResearchAreaScience & Technology - Other Topics-
dc.relation.journalWebOfScienceCategoryMultidisciplinary Sciences-
dc.description.journalRegisteredClassscie-
dc.description.journalRegisteredClassscopus-
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