Slobodyansky E, Aoki Y, Gaznabi A K, Aviles D H, Fildes R D, Jose P A
Georgetown University Children's Medical Center, Washington, District of Columbia 20007.
Am J Physiol. 1995 Feb;268(2 Pt 2):F279-84. doi: 10.1152/ajprenal.1995.268.2.F279.
In the brain, dopamine, via protein kinase A (PKA) activation of dopamine- and cAMP-regulated phosphoprotein (DARPP-32), inhibits protein phosphatase 1 (PP1) activity and keeps Na(+)-K(+)-adenosinetriphosphatase (ATPase) in its phosphorylated inactive state. In the present study, we examined the relationship among dopamine, PP1, and Na(+)-K(+)-ATPase activities in renal proximal tubules. PP1 activity in proximal tubules was not decreased by dopamine (5 x 10(-9)-10(-4) M), fenoldopam (5 x 10(-6) M), or norepinephrine (5 x 10(-7) M). In contrast, in the medullary thick ascending limb of Henle and in the brain striatum, PP1 activity was decreased by fenoldopam (5 x 10(-6) M). We also showed that the ability of dopamine (10(-6) M) to inhibit Na(+)-K(+)-ATPase activity in proximal tubules (assessed by ouabain-sensitive 86Rb uptake) occurred in the absence or presence of a sodium clamp with 5 microM monensin. Thus the inhibitory effect of dopamine on Na(+)-K(+)-ATPase activity in proximal tubules is not regulated by PP1 activity. Tautomycin and okadaic acid by themselves, at concentrations that inhibited PP1 activity, had no effect on Na(+)-K(+)-ATPase activity in proximal tubules. The ability of a dopamine D1 agonist, fenoldopam, to inhibit PP1 activity in brain striatum and in medullary thick ascending limb, but not in proximal tubules, suggests differential organ and nephron segment regulation of PP activity.
在大脑中，多巴胺通过蛋白激酶A（PKA）激活多巴胺和环磷酸腺苷调节的磷蛋白（DARPP - 32），抑制蛋白磷酸酶1（PP1）的活性，并使钠钾三磷酸腺苷酶（ATPase）保持在磷酸化的非活性状态。在本研究中，我们检测了肾近端小管中多巴胺、PP1和钠钾ATP酶活性之间的关系。多巴胺（5×10⁻⁹ - 10⁻⁴ M）、非诺多泮（5×10⁻⁶ M）或去甲肾上腺素（5×10⁻⁷ M）均未降低近端小管中的PP1活性。相比之下，在髓袢升支粗段和脑纹状体中，非诺多泮（5×10⁻⁶ M）可降低PP1活性。我们还发现，无论有无5 μM莫能菌素的钠钳制，多巴胺（10⁻⁶ M）抑制近端小管中钠钾ATP酶活性（通过哇巴因敏感的⁸⁶Rb摄取评估）的能力均存在。因此，多巴胺对近端小管中钠钾ATP酶活性的抑制作用不受PP1活性的调节。在抑制PP1活性的浓度下，互隔交链孢酚单甲醚和冈田酸单独作用时，对近端小管中的钠钾ATP酶活性没有影响。多巴胺D1激动剂非诺多泮能够抑制脑纹状体和髓袢升支粗段中的PP1活性，但不能抑制近端小管中的PP1活性，这表明PP活性存在器官和肾单位节段的差异调节。
