D4 dopamine receptor enhances angiotensin II-stimulated aldosterone secretion through PKC-ε and calcium signaling

Abstract

-Aldosterone secretion is subjected to dopaminergic regulation. Our previous study showed that both human D2 and D4 dopamine receptors (D2R and D4R) modulate aldosterone secretion, but in opposing directions. The inhibitory effect of D2R is mediated by attenuating protein kinase C-(PKC-) and calcium-dependent signaling. The mechanism of D4R effect on angiotensin II (AII)-stimulated aldosterone secretion is explored in this study. Experiments were done with primary human adrenal cortical cells and human adrenocarcinoma (NCI-H295R) cells. Activation of different PKC isoforms was detected by specific phospho-PKC antibodies and PKC translocation. The role of calciumdependent signaling was examined by measuring the cytoplasmic inositol 1,4,5-triphosphate (IP3) and calcium ([Ca 2ϩ ]i). The D4R agonist PD-168,077 enhanced AII-stimulated aldosterone synthesis and secretion as early as 30 min following exposure independently of the modulation of aldosterone synthase (CYP11B2) transcription. CYP11B2 mRNA level elevated by AII was augmented by D4R in the later period. These effects were reversed by the D4R antagonist L-745,870. AII activated PKC-␣/␤II, -ε, and -but not PKC-␦, -, or -/ of H295R cells. The D4R agonist selectively enhanced AIIstimulated PKC-ε phosphorylation and its translocation to the cell membrane. Furthermore, the D4R agonist enhanced the AII-stimulated elevation of intracellular IP 3 and [Ca 2ϩ ]i. Inhibition of PKC-ε translocation by the PKC-ε-specific inhibitory peptide attenuated AII-stimulated aldosterone secretion, CYP11B2 mRNA expression, and elevation of intracellular IP 3 and [Ca 2ϩ ]i. We conclude that D4R augmented aldosterone synthesis/secretion induced by AII. The mechanisms responsible for this augmentation are mediated through enhancing PKC-ε phosphorylation and [Ca 2ϩ ]i elevation.aldosterone-producing adenoma; protein kinase C-ε; hypertension THERE IS INCREASING EVIDENCE (8, 12) that aldosterone plays a direct role in the pathogenesis of chronic heart failure and vascular inflammation. The vascular and perivascular inflammatory responses to angiotensin II (AII) infusion and salt loading, both reported to increase cardiovascular aldosterone synthesis (28,29), are completely prevented by adrenalectomy (25). This suggests that the regulation of adrenal aldosterone production is more important than that of local cardiac and/or vascular synthesis of aldosterone. Although the regulation of aldosterone production by AII is well established, the modulating factors affecting itself or its downstream signaling are controversial and far from being completely delineated. The presence of chromaffin cells originating from the medulla in the cortical layers is strong evidence supporting the concept of the neurohormonal control of zona glomerulosa cell secretion (5). Dopamine D2-like receptors have been found (9, 19) to play a pivotal role in inhibiting aldosterone secretion. We (31) and other investigators (23) have demonstrated that two subtypes of dopamine receptors, D2 and D4 receptors (D2R and D4R)...

Direct inhibition of basolateral Kir4.1/5.1 and Kir4.1 channels in the cortical collecting duct by dopamine

“…9). Activation of D 2 -like receptors has been shown to stimulate PKC in different cell types (8,14). Interestingly, PKC has been proposed to directly phosphorylate multiple intracellular residues in heteromeric K ir 4.1/5.1 channels in an expression system, leading to its inhibition (28).…”

When is high‐Ca2+ microdomain required for mitochondrial Ca2+ uptake?*

“…The effect of the inhibition of a novel isoform of PKC proved to be similar to that of p38 MAPK [In view of published data on the expression of PKC isoforms in H295R cells (Chang et al. 2008, Lehoux & Lefebvre 2006, Romero et al.…”

“…The effect of the inhibition of a novel isoform of PKC proved to be similar to that of p38 MAPK [In view of published data on the expression of PKC isoforms in H295R cells (Chang et al 2008, Lehoux & Lefebvre 2006, Romero et al 2006, PKC or l may be assumed to be the respective isoform.]. In lack of specific inhibitors of the novel isoforms, we compared the effect of the pharmacological inhibition of conventional PKC isoforms by Gö 6976 with that of the combined inhibition of conventional and novel isoforms of PKC by bisindolylmaleimide (BIS) .…”

Primary Aldosteronism: Changing Definitions and New Concepts of Physiology and Pathophysiology Both Inside and Outside the Kidney

“…Low tumor DA2 expression, however, would not explain why patients with APA have been reported to demonstrate brisk and sometimes even exaggerated responses of plasma aldosterone in response to metoclopramide (332,364,570). Adrenal cortical cellular responses to dopamine that may contribute to its inhibitory actions on aldosterone production include blockade of Ttype calcium channels (389) and reductions in PKC isoforms (89), intracellular calcium (89,169), and cAMP (329).…”