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首页> 外文期刊>Cellular Physiology and Biochemistry >Distinct signalling cascades downstream to G(s)alpha coupled dopamine D-1-like NHE3 inhibition in rat and opossum renal epithelial cells
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Distinct signalling cascades downstream to G(s)alpha coupled dopamine D-1-like NHE3 inhibition in rat and opossum renal epithelial cells

机译：在大鼠和负鼠肾上皮细胞中，G（s）alpha偶联多巴胺D-1样NHE3抑制下游不同的信号级联

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Dopamine D-1-like receptors are linked via G proteins to multiple cellular signaling pathways, namely adenylyl cyclase (AC) and phospholipase C (PLC). We have previously shown that the D-1-mediated inhibition of Na+-K+-ATPase activity in OK cells involves the sequential activation of the AC-protein kinase A (AC-PKA) and the PLC-protein kinase C (PLC-PKC) pathways. The present study evaluated signaling cascades involved in dopamine-mediated inhibition of Na+/H+ exchanger isoform 3 (NHE3) in rat and opossum renal cells. Na+/H+ exchanger activity was assayed as the initial rate of intracellular pH (pH(i)) recovery after an acid load. V-max values (in pH units/ s) for Na+-dependent pHi recovery in rat cells (0.0097 0.0007) were greater (P<0.05) those in opossum cells (0.0063 0.0007), with similar K-m values (in mM) for Na+ (rat, 35 9; opossum, 24 9). The IC50 values for EIPA and amiloride induced decrease in NHE activity in rat and opossum kidney cells are in agreement with the observation that rat renal proximal tubules and opossum kidney cells express mainly the NHE3 isoform. The D-1-like receptor agonist SKF 38393 inhibited NHE3 activity in a concentration-dependent manner in both rat and opossum cells. The D-1-mediated inhibition of NHE3 was prevented either by the D-1-like receptor antagonist SKF 83566 (1 μM), overnight treatment with cholera toxin (500 ng/ml) and the PKA antagonist H-89 (10 μM) in rat and opossum kidney cells. The effect of SKF 38393 was abolished by the PKC antagonist chelerythrine (1 μM), or the PLC inhibitor U-73,122 (3 μM) in opossum cells, but not in rat cells. In addition, dibutyril cAMP (dB-cAMP; 500 μM) was found to increase PLC activity in OK cells but not in rat cells. The effect of D-1-like dopamine agonist was accompanied by increases in cyclic AMP production in rat and opossum cells. The inhibitory effect of SKF 38393 (1 μM) on NHE3 activity was abolished in rat and opossum cells pre-treated with the anti-G(s)α antibody, but not in cells treated with the anti-G(q/11)α antibody. It is concluded that D-1 agonists decrease NHE3 activity by classical stimulation of AC and PKA via G(s)α proteins in rat kidney cells. By contrast, the D-1-mediated inhibition of NHE3 in renal opossum cells involves a peculiar mechanism with AC-PKA and PLC-PKC pathways. Copyright (C) 2004 S. Karger AG, Basel.
机译：多巴胺D-1样受体通过G蛋白与多种细胞信号通路相连，即腺苷酸环化酶（AC）和磷脂酶C（PLC）。我们以前已经证明，D-1介导的OK细胞对Na + -K + -ATPase活性的抑制涉及AC蛋白激酶A（AC-PKA）和PLC蛋白激酶C（PLC-PKC）的顺序激活。途径。本研究评估了大鼠和负鼠肾细胞中多巴胺介导的Na + / H +交换异构体3（NHE3）抑制的信号级联反应。将Na + / H +交换子活性测定为酸加载后细胞内pH（pH（i））恢复的初始速率。大鼠细胞（0.0097 0.0007）中Na +依赖的pHi恢复的V-max值（以pH单位/ s为单位）（0.0063 0.0007）更大（P <0.05），负鼠细胞中Na +依赖的pHi恢复的V-max（P <0.05），Na +的Km值（mM）相似（大鼠35 9;负鼠24 9）。 EIPA和阿米洛利引起的大鼠和负鼠肾细胞NHE活性降低的IC50值与观察到的大鼠肾近端肾小管和负鼠肾细胞主要表达NHE3亚型相一致。 D-1样受体激动剂SKF 38393在大鼠和负鼠细胞中均以浓度依赖的方式抑制NHE3活性。 D-1样受体拮抗剂SKF 83566（1μM），霍乱毒素（500 ng / ml）和PKA拮抗剂H-89（10μM）过夜治疗可预防D-1介导的NHE3抑制。在大鼠和负鼠肾细胞中在负鼠细胞中，PKC拮抗剂白屈菜红碱（1μM）或PLC抑制剂U-73,122（3μM）消除了SKF 38393的作用，但在大鼠细胞中却没有。此外，发现丁二腈cAMP（dB-cAMP; 500μM）可以增加OK细胞的PLC活性，但不能增加大鼠细胞的PLC活性。 D-1样多巴胺激动剂的作用伴随着大鼠和负鼠细胞中环AMP产生的增加。在用抗G（s）α抗体预处理的大鼠和负鼠细胞中，消除了SKF 38393（1μM）对NHE3活性的抑制作用，但在抗G（q / 11）α处理的细胞中却没有抗体。结论是D-1激动剂通过大鼠肾细胞中G（s）α蛋白通过经典刺激AC和PKA降低NHE3活性。相比之下，D-1介导的对肾脏负鼠细胞中NHE3的抑制涉及具有AC-PKA和PLC-PKC途径的独特机制。版权所有（C）2004 S.Karger AG，巴塞尔。

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