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Critical role of parathyroid hormone (PTH) receptor-1 phosphorylation in regulating acute responses to PTH
Akira Maeda, Makoto Okazaki, David M. Baron, Thomas Dean, Ashok Khatri, Mathew Mahon, Hiroko Segawa, Abdul B. Abou-Samra, Harald Jüppner, Kenneth D. Bloch, John T. Potts, Jr. and Thomas J. Gardella
Proceedings of the National Academy of Sciences of the United States of America
Vol. 110, No. 15 (April 9, 2013), pp. 5864-5869
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/42590320
Page Count: 6
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Agonist-induced phosphorylation of the parathyroid hormone (PTH) receptor 1 (PTHR1) regulates receptor signaling in vitro, but the role of this phosphorylation in vivo is uncertain. We investigated this role by injecting "knock-in" mice expressing a phosphorylation-deficient (PD) PTHR1 with PTH ligands and assessing acute biologic responses. Following injection with PTH (1-34), or with a unique, long-acting PTH analog, PD mice, compared with WT mice, exhibited enhanced increases in cAMP levels in the blood, as well as enhanced cAMP production and gene expression responses in bone and kidney tissue. Surprisingly, however, the hallmark hypercalcemie and hypophosphatemic responses were markedly absent in the PD mice, such that paradoxical hypocalcémie and hyperphosphatemic responses were observed, quite strikingly with the long-acting PTH analog. Spot urine analyses revealed a marked defect in the capacity of the PD mice to excrete phosphate, as well as cAMP, into the urine in response to PTH injection. This defect in renal excretion was associated with a severe, PTH-induced impairment in glomerular filtration, as assessed by the rate of FITC-inulin clearance from the blood, which, in turn, was explainable by an overly exuberant systemic hypotensive response. The overall findings demonstrate the importance in vivo of PTH-induced phosphorylation of the PTHR1 in regulating acute ligand responses, and they serve to focus attention on mechanisms that underlie the acute calcémie response to PTH and factors, such as blood phosphate levels, that influence it.
Proceedings of the National Academy of Sciences of the United States of America © 2013 National Academy of Sciences