Regulation of prostaglandin EP1 and EP4 receptor signaling by carrier-mediated ligand reuptake

被引:8
|
作者
Chi, Yuling [1 ]
Suadicani, Sylvia O. [2 ,3 ]
Schuster, Victor L. [1 ,4 ]
机构
[1] Albert Einstein Coll Med, Dept Med, 1300 Morris Pk Ave, Bronx, NY 10461 USA
[2] Albert Einstein Coll Med, Dept Urol, Bronx, NY 10461 USA
[3] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA
[4] Albert Einstein Coll Med, Dept Physiol & Biophys, Bronx, NY 10461 USA
来源
PHARMACOLOGY RESEARCH & PERSPECTIVES | 2014年 / 2卷 / 05期
基金
美国国家卫生研究院;
关键词
Eicosanoids; G-protein-coupled receptors; prostaglandins; signal transduction; SLCO2A1;
D O I
10.1002/prp2.51
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
After synthesis and release from cells, prostaglandin E-2 (PGE(2)) undergoes reuptake by the prostaglandin transporter (PGT), followed by cytoplasmic oxidation. Although genetic inactivation of PGT in mice and humans results in distinctive phenotypes, and although experiments in localized environments show that manipulating PGT alters downstream cellular events, a direct mechanistic link between PGT activity and PGE(2) (EP) receptor activation has not been made. Toward this end, we created two reconstituted systems to examine the effect of PGT expression on PGE(2) signaling via two of its receptors (EP1 and EP4). In human embryonic kidney cells engineered to express the EP1 receptor, exogenous PGE(2) induced a dose-dependent increase in cytoplasmic Ca2+. When PGT was expressed at the plasma membrane, the PGE(2) doseresponse curve was right-shifted, consistent with reduction in cell surface PGE(2) availability; a potent PGT inhibitor acutely reversed this shift. When bradykinin was used to induce endogenous PGE(2) release, PGT expression similarly induced a reduction in Ca2+ responses. In separate experiments using Madin-Darby Canine Kidney cells engineered to express the PGE(2) receptor EP4, bradykinin again induced autocrine PGE(2) signaling, as judged by an abrupt increase in intracellular cAMP. As in the EP1 experiments, expression of PGT at the plasma membrane caused a reduction in bradykinin-induced cAMP accumulation. Pharmacological concentrations of exogenous PGE(2) induced EP4 receptor desensitization, an effect that was mitigated by PGT. Thus, at an autocrine/paracrine level, plasma membrane PGT regulates PGE(2) signaling by decreasing ligand availability at cell surface receptors.
引用
收藏
页数:11
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