Ca2+ allostery in PTH-receptor signaling
- Authors
- White, Alex D.; Fang, Fei; Jean-Alphonse, Frederic G.; Clark, Lisa J.; An, Hyun-Jung; Liu, Hongda; Zhao, Yang; Reynolds, Shelley L.; Lee, Sihoon; Xiao, Kunhong; Sutkeviciute, Ieva; Vilardaga, Jean-Pierre
- Issue Date
- 19-Feb-2019
- Publisher
- NATL ACAD SCIENCES
- Keywords
- PTH; PTH receptor; GPCR signaling; Ca2+ allosterism; endosomal cAMP signaling
- Citation
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.116, no.8, pp.3294 - 3299
- Journal Title
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
- Volume
- 116
- Number
- 8
- Start Page
- 3294
- End Page
- 3299
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/1835
- DOI
- 10.1073/pnas.1814670116
- ISSN
- 0027-8424
- 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.
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