Role of Phospholipase D in Parathyroid Hormone Type 1 Receptor Signaling and Trafficking

被引:21
|
作者
Garrido, Jose Luis [1 ]
Wheeler, David [1 ,2 ]
Vega, Luis Leiva [1 ]
Friedman, Peter A. [1 ]
Romero, Guillermo [1 ]
机构
[1] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Sch Med, Pittsburgh, PA 15261 USA
[2] Univ Pittsburgh, Med Scientist Training Program, Sch Med, Pittsburgh, PA 15261 USA
基金
美国国家卫生研究院;
关键词
ADP-RIBOSYLATION FACTOR; ACTIVATED PROTEIN-KINASE; SMOOTH-MUSCLE-CELLS; PHOSPHATIDIC-ACID; PLASMA-MEMBRANE; ANGIOTENSIN-II; GROWTH-FACTOR; OSTEOBLASTIC CELLS; COUPLED-RECEPTORS; DOWN-REGULATION;
D O I
10.1210/me.2008-0436
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The role of phospholipase D (PLD) in the regulation of the traffic of the PTH type 1 receptor (PTH1R) was studied in Chinese hamster ovary cells stably transfected with a human PTH1R (CHO-R3) and in rat osteosarcoma 17/2.8 (ROS) cells. PTH(1-34) increased total PLD activity by 3-fold in CHO-R3 cells and by 2-fold in ROS cells. Overexpression of wild-type (WT) PLD1 and WT-PLD2 increased basal PLD activity in CHO-R3 but not in ROS cells. Ligand-stimulated PLD activity greatly increased in CHO-R3 cells transfected with WT-PLD1 and WT-PLD2. However, only WT-PLD2 expression increased PTH-dependent PLD activity in ROS cells. Expression of the catalytically inactive mutants R898K-PLD1 (DN-PLD1) and R758K-PLD2 (DN-PLD2) inhibited ligand-dependent PLD activity in both cell lines. PTH(1-34) induced internalization of the PTH1R with a concomitant increase in the colocalization of the receptor with PLD1 in intracellular vesicles and in a perinuclear, ADP ribosylation factor-1-positive compartment. The distribution of PLD1 and PLD2 remained unaltered after PTH treatment. Expression of DN-PLD1 had a small effect on endocytosis of the PTH1R; however, DN-PLD1 prevented accumulation of the PTH1R in the perinuclear compartment. Expression of DN-PLD2 significantly retarded ligand-induced PTH1R internalization in both cell lines. The differential effects of PLD1 and PLD2 on receptor traffic were confirmed using isoform-specific short hairpin RNA constructs. We conclude that PLD1 and PLD2 play distinct roles in regulating PTH1R traffic; PLD2 primarily regulates endocytosis, whereas PLD1 regulates receptor internalization and intracellular receptor traffic. (Molecular Endocrinology 23: 2048-2059, 2009)
引用
收藏
页码:2048 / 2059
页数:12
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