Constitutive activation of the cyclic adenosine 3',5'-monophosphate signaling pathway by parathyroid hormone (PTH)/PTH-related peptide receptors mutated at the two loci for Jansen's metaphyseal chondrodysplasia

Molecular Endocrinology
E SchipaniH Jüppner

Abstract

Two different activating PTH/PTH-related peptide (PTHrP) receptor mutations, H223R and T410P, were recently identified as the most likely cause of Jansen's metaphyseal chondrodysplasia. To assess the functional importance of either amino acid position in the human PTH/PTHrP receptor, H223 and T410 were individually replaced by all other amino acids. At position 223, only arginine and lysine led to agonist-independent cAMP accumulation; all other amino acid substitutions resulted in receptor mutants that lacked constitutive activity or were uninformative due to poor cell surface expression. In contrast, most amino acid substitutions at position 410 conferred constitutive cAMP accumulation and affected PTH/PTHrP receptor expression not at all or only mildly. Mutations corresponding to the H223R or T410P exchange in the human PTH/PTHrP receptor also led to constitutive activity when introduced into the opossum receptor homolog, but showed little or no change in basal cAMP accumulation when introduced into the rat PTH/PTHrP receptor. The PTH/PTHrP receptor residues mutated in Jansen's disease are conserved in all mammalian members of this family of G protein-coupled receptors. However, when the equivalent of either the H223R or the...Continue Reading

References

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Citations

Aug 30, 2000·Proceedings of the National Academy of Sciences of the United States of America·S M NielsenW W Vale
Dec 12, 2001·Molecular Biology of the Cell·F BeierP LuValle
Oct 16, 2008·The Journal of Clinical Endocrinology and Metabolism·Whitney W BrownKenneth L McCormick
Jan 24, 1998·Molecular Endocrinology·S A HjorthT W Schwartz
Sep 18, 2020·Scientific Reports·Steven P D HarborneAdrian Goldman
Jun 3, 2021·Genes·Anna PapadopoulouFotini-Eleni Karachaliou

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