Submitted on June 22, 2007
Accepted on July 3, 2007
Sphingosine 1-phosphate stimulates aldosterone secretion through a mechanism involving the PI3-kinase/PKB and MEK/ERK 1/2 pathways
Leyre Brizuela, Miriam Rábano, Patricia Gangoiti, Natalia Narbona, José María Macarulla, Miguel Trueba, and Antonio Gómez-Muñoz
Biochemistry and Molecular Biology, University of the Basque Country, Bilbao, Bizkaia 48080
Corresponding Author: antonio.gomez{at}ehu.es
We reported recently that sphingosine 1-phosphate (S1P) is a novel regulator of aldosterone secretion in zona glomerulosa cells of adrenal glands, and that phospholipase D (PLD) is implicated in this process. We now show that S1P causes phosphorylation of protein kinase B (PKB) and extracellularly regulated kinases 1/2 (ERK1/2), which is an indication of their activation, in these cells. These effects are probably mediated through interaction of S1P with the Gi protein-coupled receptors S1P1/3, as pre-treatment with pertussis toxin or with the S1P1/3 antagonist VPC 23019 completely abolished phosphorylation of these kinases. Inhibitors of phosphatidylinositol 3-kinase (PI3K) or mitogen-activated kinase kinase (MEK) blocked S1P-stimulated aldosterone secretion. This inhibition was only partial when the cells were incubated independently with inhibitors of each pathway. However, aldosterone output was completely blocked when the cells were pre-treated with LY294002 and PD98059, simultaneously. These inhibitors also blocked PLD activation, which indicates that this enzyme is downstream of PI3K and MEK in this system. We propose a working model for S1P in which stimulation of the PI3K/PKB and MEK/ERK pathways leads to stimulation of PLD and aldosterone secretion.
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