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Beta-arrestin-dependent parathyroid hormone-stimulated extracellular signal-regulated kinase activation and

W Bruce Sneddon1, Peter A Friedman

  • 1Department of Pharmacology, Renal Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.

Endocrinology
|May 26, 2007
PubMed

Insights

Parathyroid hormone (PTH) regulates calcium by activating ERK1/2 in kidney cells. This process involves beta-arrestin (betaAr) and receptor internalization, with betaAr1 and betaAr2 playing distinct roles in sustained ERK activation.

Area of Science:

  • Nephrology
  • Endocrinology
  • Cellular Signaling

Background:

  • Parathyroid hormone (PTH) is crucial for regulating renal calcium homeostasis.
  • PTH acts on the distal nephron, and its effects in distal convoluted tubule (DCT) cells involve ERK1/2 activation.
  • Beta-adrenergic receptor (beta-AR) activation exhibits biphasic ERK signaling dependent on beta-arrestin (betaAr) and receptor internalization.

Purpose of the Study:

  • To investigate the characteristics of PTH-stimulated ERK activation in DCT cells.
  • To determine the involvement of receptor internalization and beta-arrestin dependence in PTH signaling.
  • To elucidate the specific roles of beta-arrestin 1 (betaAr1) and beta-arrestin 2 (betaAr2) in PTH-induced ERK activation.

Main Methods:

  • Assessed PTH-stimulated ERK activation in mouse DCT cells.
  • Utilized mouse embryonic fibroblasts (MEFs) from betaAr1- and betaAr2-null mice to study betaAr dependence.
  • Examined the impact of the betaAr1 clathrin-binding domain and NHERF1 coexpression on PTH receptor (PTH1R) internalization and ERK activation.

Main Results:

  • PTH induced a rapid, transient ERK activation in DCT cells, peaking at 5 minutes.
  • In wild-type MEFs, PTH-stimulated ERK activation was sustained, whereas in betaAr1/betaAr2-null MEFs, it returned to baseline rapidly.
  • ERK activation was delayed and prolonged in betaAr1-null MEFs, indicating a role for betaAr1 in the transient phase.
  • PTH1R internalization was not inhibited by the betaAr1 clathrin-binding domain alone but was blocked by coexpression with NHERF1.
  • A betaAr2-dependent late phase of ERK activation was observed, requiring PTH1R internalization.

Conclusions:

  • PTH-stimulated ERK activation in DCT cells has a rapid, transient phase potentially involving betaAr1.
  • A distinct, prolonged ERK activation phase mediated by PTH is dependent on betaAr2 and involves PTH1R internalization.

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