Blazer-Yost B L, Hughes C L, Nolan P L
Biology Department, Indiana University/Purdue University at Indianapolis, USA.
Am J Physiol. 1997 Jun;272(6 Pt 1):C1928-35. doi: 10.1152/ajpcell.1997.272.6.C1928.
Aldosterone stimulation of transcellular Na+ flux in polarized epithelial cells is dependent on at least one transmethylation reaction, but the substrate of this signaling step is unknown. Because it is clear that the majority of cellular protein methylation occurs in conjunction with protein prenylation, we examined the importance of prenylation to aldosterone-stimulated Na+ transport in the A6 cell line. Lovastatin, an inhibitor of the first committed step of the mevalonate pathway, inhibits the natriferic effect of aldosterone but does not inhibit insulin-stimulated Na+ flux. The addition of a farnesyl group does not appear to be involved in aldosterone's action. Neither alpha-hydroxyfarne-sylphosphonic acid, an inhibitor of farnesyl:protein transferase, nor N-acetyl-S-farnesyl-L-cysteine, an inhibitor of farnesylated protein methylation, inhibits the hormone-induced increase in Na+ transport. In contrast, N-acetyl-S-geranyl-geranyl-L-cysteine, an inhibitor of geranylgeranyl protein methylation, completely abolishes the aldosterone-induced increase in Na+ flux with no effect on insulin-mediated Na+ transport or cellular protein content. These data indicate that methylation of a geranylgeranylated protein is involved in aldosterone's natriferic action.
醛固酮对极化上皮细胞跨细胞钠离子通量的刺激作用至少依赖于一种转甲基化反应，但其信号转导步骤的底物尚不清楚。鉴于大多数细胞蛋白甲基化显然是与蛋白异戊二烯化同时发生的，我们研究了异戊二烯化对A6细胞系中醛固酮刺激的钠离子转运的重要性。洛伐他汀是甲羟戊酸途径第一步的抑制剂，它能抑制醛固酮的促钠排泄作用，但不抑制胰岛素刺激的钠离子通量。添加法尼基似乎与醛固酮的作用无关。法尼基：蛋白转移酶抑制剂α-羟基法尼基膦酸和法尼基化蛋白甲基化抑制剂N-乙酰-S-法尼基-L-半胱氨酸均不抑制激素诱导的钠离子转运增加。相反，香叶基香叶基蛋白甲基化抑制剂N-乙酰-S-香叶基香叶基-L-半胱氨酸完全消除了醛固酮诱导的钠离子通量增加，而对胰岛素介导的钠离子转运或细胞蛋白含量无影响。这些数据表明，香叶基香叶基化蛋白的甲基化参与了醛固酮的促钠排泄作用。
