Intracellular Na⁺ Regulates Dopamine and Angiotensin II Receptors Availability at the Plasma Membrane and Their Cellular Responses in Renal Epithelia*

Abstract

The balance and cross-talk between natruretic and antinatruretic hormone receptors plays a critical role in the regulation of renal Na⁺ homeostasis, which is a major determinant of blood pressure. Dopamine and angiotensin II have antagonistic effects on renal Na⁺ and water excretion, which involves regulation of the Na⁺,K⁺-ATPase activity. Herein we demonstrate that angiotensin II (Ang II) stimulation of AT1 receptors in proximal tubule cells induces the recruitment of Na⁺,K⁺-ATPase molecules to the plasmalemma, in a process mediated by protein kinase Cβ and interaction of the Na⁺,K⁺-ATPase with adaptor protein 1. Ang II stimulation led to phosphorylation of the α subunit Ser-11 and Ser-18 residues, and substitution of these amino acids with alanine residues completely abolished the Ang II-induced stimulation of Na⁺,K⁺-ATPase-mediated Rb⁺ transport. Thus, for Ang II-dependent stimulation of Na⁺,K⁺-ATPase activity, phosphorylation of these serine residues is essential and may constitute a triggering signal for recruitment of Na⁺,K⁺-ATPase molecules to the plasma membrane. When cells were treated simultaneously with saturating concentrations of dopamine and Ang II, either activation or inhibition of the Na⁺,K⁺-ATPase activity was produced dependent on the intracellular Na⁺ concentration, which was varied in a very narrow physiological range (9–19 mm). A small increase in intracellular Na⁺ concentrations induces the recruitment of D1 receptors to the plasma membrane and a reduction in plasma membrane AT1 receptors. Thus, one or more proteins may act as an intracellular Na⁺ concentration sensor and play a major regulatory role on the effect of hormones that regulate proximal tubule Na⁺ reabsorption.