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Dual Regulation of the Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Signaling by Protein Kinase C and ß-Arrestins

Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078, Germany

Address all correspondence and requests for reprints to: Martin J. Lohse, Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078, Germany. E-mail: lohse{at}toxi.uni-wuerzburg.de.

We examined here the role of second messenger-dependent kinases and ß-arrestins in short-term regulation of the PTH receptor (PTHR) signaling. The inhibition of protein kinase C (PKC) in COS-7 cells transiently expressing PTHR, led to an approximately 2-fold increase in PTH-stimulated inositol phosphate (IP) and cAMP production. The inhibition of protein kinase A increased cAMP production 1.5-fold without affecting IP signaling. The effects of PKC inhibition on PTHR-mediated G_q signaling were strongly decreased for a carboxy-terminally truncated PTHR (T480) that is phosphorylation deficient. PKC inhibition was associated with a decrease in agonist-stimulated PTHR phosphorylation and internalization without blocking PTH-dependent mobilization of ß-arrestin2 to the plasma membrane. Overexpression of ß-arrestins strongly decreased the PTHR-mediated IP signal, whereas cAMP production was impaired to a much lower extent. The regulation of PTH-stimulated signals by ß-arrestins was impaired for the truncated T480 receptor.

Our data reveal mechanisms at, and distal to, the receptor regulating PTHR-mediated signaling pathways by second messenger-dependent kinases. We conclude that regulation of PTHR-mediated signaling by PKC and ß-arrestins are separable phenomena that both involve the carboxy terminus of the receptor. A major role for PKC and ß-arrestins in preferential regulation of PTHR-mediated G_q signaling by independent mechanisms at the receptor level was established.

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