Ca2+ allostery in PTH-receptor signaling
DC Field | Value | Language |
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dc.contributor.author | White, Alex D. | - |
dc.contributor.author | Fang, Fei | - |
dc.contributor.author | Jean-Alphonse, Frederic G. | - |
dc.contributor.author | Clark, Lisa J. | - |
dc.contributor.author | An, Hyun-Jung | - |
dc.contributor.author | Liu, Hongda | - |
dc.contributor.author | Zhao, Yang | - |
dc.contributor.author | Reynolds, Shelley L. | - |
dc.contributor.author | Lee, Sihoon | - |
dc.contributor.author | Xiao, Kunhong | - |
dc.contributor.author | Sutkeviciute, Ieva | - |
dc.contributor.author | Vilardaga, Jean-Pierre | - |
dc.date.available | 2020-02-27T04:41:29Z | - |
dc.date.created | 2020-02-05 | - |
dc.date.issued | 2019-02-19 | - |
dc.identifier.issn | 0027-8424 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/1835 | - |
dc.description.abstract | The 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.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | NATL ACAD SCIENCES | - |
dc.relation.isPartOf | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | - |
dc.subject | PROTEIN-COUPLED RECEPTORS | - |
dc.subject | PARATHYROID-HORMONE | - |
dc.subject | AGONIST BINDING | - |
dc.subject | CAMP | - |
dc.subject | MG2+ | - |
dc.subject | GENERATION | - |
dc.subject | RETROMER | - |
dc.title | Ca2+ allostery in PTH-receptor signaling | - |
dc.type | Article | - |
dc.type.rims | ART | - |
dc.description.journalClass | 1 | - |
dc.identifier.wosid | 000459074400074 | - |
dc.identifier.doi | 10.1073/pnas.1814670116 | - |
dc.identifier.bibliographicCitation | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.116, no.8, pp.3294 - 3299 | - |
dc.identifier.scopusid | 2-s2.0-85061873534 | - |
dc.citation.endPage | 3299 | - |
dc.citation.startPage | 3294 | - |
dc.citation.title | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | - |
dc.citation.volume | 116 | - |
dc.citation.number | 8 | - |
dc.contributor.affiliatedAuthor | An, Hyun-Jung | - |
dc.contributor.affiliatedAuthor | Lee, Sihoon | - |
dc.type.docType | Article | - |
dc.subject.keywordAuthor | PTH | - |
dc.subject.keywordAuthor | PTH receptor | - |
dc.subject.keywordAuthor | GPCR signaling | - |
dc.subject.keywordAuthor | Ca2+ allosterism | - |
dc.subject.keywordAuthor | endosomal cAMP signaling | - |
dc.subject.keywordPlus | PROTEIN-COUPLED RECEPTORS | - |
dc.subject.keywordPlus | PARATHYROID-HORMONE | - |
dc.subject.keywordPlus | AGONIST BINDING | - |
dc.subject.keywordPlus | CAMP | - |
dc.subject.keywordPlus | MG2+ | - |
dc.subject.keywordPlus | GENERATION | - |
dc.subject.keywordPlus | RETROMER | - |
dc.relation.journalResearchArea | Science & Technology - Other Topics | - |
dc.relation.journalWebOfScienceCategory | Multidisciplinary Sciences | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
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