Dual regulation of the parathyroid hormone (PTH)/PTH-related peptide receptor signaling by protein kinase C and beta-arrestins.
We examined here the role of second messenger-dependent kinases and beta-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 beta-arrestin2 to the plasma membrane. Overexpression of beta-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 beta-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 beta-arrestins are separable phenomena that both involve the carboxy terminus of the receptor. A major role for PKC and beta-arrestins in preferential regulation of PTHR-mediated G(q) signaling by independent mechanisms at the receptor level was established.
Castro
Marián
M
Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, Germany.
Dicker
Frank
F
Vilardaga
Jean-Pierre
JP
Krasel
Cornelius
C
Bernhardt
Manfred
M
Lohse
Martin J
MJ
D000818:Animals; D019390:Arrestins / Q000494:pharmacology / Q000502:physiology*; D019556:COS Cells; D000242:Cyclic AMP / Q000502:physiology; D007295:Inositol Phosphates / Q000502:physiology; D010281:Parathyroid Hormone / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D010770:Phosphotransferases / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology*; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D000071557:beta-Arrestins
D019390:Arrestins; D007295:Inositol Phosphates; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D000071557:beta-Arrestins; D000242:Cyclic AMP; D010770:Phosphotransferases; D011493:Protein Kinase C