Ca²⁺ allostery in PTH-receptor signaling.

ABSTRACT: The parathyroid hormone (PTH) and its related peptide (PTHrP) activate PTH receptor (PTHR) signaling, but only the PTH sustains G_S-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 th

SUBMITTER: White AD 

PROVIDER: S-EPMC6386702 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature