Efendiev Riad, Pedemonte Carlos H
University of Houston, College of Pharmacy, 4800 Calhoun Boulevard, Houston, TX 77204-5037, USA.
J Am Soc Nephrol. 2006 Jan;17(1):31-8. doi: 10.1681/ASN.2005070681. Epub 2005 Dec 7.
Renal sodium homeostasis is a major determinant of BP and is regulated by several natriuretic and antinatriuretic hormones. These hormones, acting through intracellular secondary messengers, either activate or inhibit proximal tubule Na,K-ATPase. It was shown previously that phorbol esters and angiotensin II and serotonin induce the phosphorylation of both Ser-11 and Ser-18 of the Na,K-ATPase alpha-subunit. This results in the recruitment of Na,K-ATPase molecules to the plasma membrane and an increased capacity to transport sodium ions. Treatment of the same cells with dopamine leads to phosphorylation of the Na,K-ATPase alpha-subunit Ser-18. The subsequent internalization of Na,K-ATPase molecules results in a reduced capacity to transport sodium ions. These effects are observed in cells that express the rat-type Na,K-ATPase. However, the Na,K-ATPase alpha1-subunit of several species, such as human, pig, and mouse, does not have a Ser-18 in their N-terminal region. Therefore, the possibility exists that, in those species, the Na,K-ATPase is not regulated by the hormones that regulate natriuresis. This study presents evidence that in cells that express the human-type Na,K-ATPase, dopamine inhibits and phorbol esters activate the Na,K-ATPase-mediated transport. These opposite effects are mediated by the phosphorylation of the same amino acid residue, Ser-11 of Na,K-ATPase alpha1, and the presence of alpha1 Ser-18 is not essential for the hormonal regulation of Na,K-ATPase activity in LLCPK1 cells. It was observed that, whereas the regulatory stimulation of Na,K-ATPase is mediated by protein kinase Cbeta, the regulatory inhibition is mediated by protein kinase Czeta. This is similar to what was demonstrated previously in cells that express the rat-type Na,K-ATPase.
肾钠稳态是血压的主要决定因素，并受多种利钠和抗利钠激素调节。这些激素通过细胞内第二信使发挥作用，激活或抑制近端小管钠钾ATP酶。先前研究表明，佛波酯、血管紧张素II和5-羟色胺可诱导钠钾ATP酶α亚基的Ser-11和Ser-18磷酸化。这导致钠钾ATP酶分子募集到质膜，钠离子转运能力增强。用多巴胺处理相同细胞会导致钠钾ATP酶α亚基Ser-18磷酸化。随后钠钾ATP酶分子内化，导致钠离子转运能力降低。这些效应在表达大鼠型钠钾ATP酶的细胞中观察到。然而，几种物种（如人类、猪和小鼠）的钠钾ATP酶α1亚基在其N端区域没有Ser-18。因此，在这些物种中，钠钾ATP酶可能不受调节利钠的激素调控。本研究提供证据表明，在表达人类型钠钾ATP酶的细胞中，多巴胺抑制而佛波酯激活钠钾ATP酶介导的转运。这些相反的效应由相同氨基酸残基（钠钾ATP酶α1的Ser-11）的磷酸化介导，并且α1 Ser-18的存在对于LLCPK1细胞中钠钾ATP酶活性的激素调节并非必需。据观察，虽然钠钾ATP酶的调节性刺激由蛋白激酶Cβ介导，但调节性抑制由蛋白激酶Cζ介导。这与先前在表达大鼠型钠钾ATP酶的细胞中所证明的情况相似。
