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Phosphorylation of PTHR1 regulates responses to PTH in vivo



DOI:10.1038/bonekey.2013.188

Maeda et al used mice engineered to express phosphorylation-deficient (PD) parathyroid hormone receptor 1 (PTHR1) to investigate the in vivo role of the PTH agonist-induced phosphorylation known to occur in vitro.

The ‘knock-in’ PD mice and controls were injected with two PTH ligands; PTH (1–34) or a long-acting analog of PTH. PD mice showed greater increases in blood cyclic AMP (cAMP) levels compared to controls and also showed elevated cAMP production and gene expression in kidney and bone tissue.

An unexpected finding was that instead of showing the hypercalcemia and hypophosphatemia observed in control mice, the PD mice became hypocalcemic and hyperphosphatemic. This response, which was secondary to the renal failure induced by hypotension, was particularly marked in PD mice given the long-acting PTH analog. PD mice were found to be unable to excrete cAMP and phosphate into their urine after receiving an injection of the PTH analog.

Editor’s comment: PTH/PTHR1 receptor phosphorylation in response to PTH agonists is crucial for the interaction between the receptor and the cytoplasmic proteins that prompt its internalization. This, in turn, regulates intracellular signaling. This elegant study demonstrates the consequences of disrupting these mechanisms in vivo, notably demonstrating that cAMP signaling exacerbates the hypotensive activity of PTH.


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