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Journal of Lipid Research, Vol. 48, 2264-2274, October 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Sphingosine-1-phosphate stimulates aldosterone secretion through a mechanism involving the PI3K/PKB and MEK/ERK 1/2 pathways

Leyre Brizuela, Miriam Rábano, Patricia Gangoiti, Natalia Narbona, José María Macarulla, Miguel Trueba and Antonio Gómez-Muñoz¹

Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country, 48080 Bilbao, Spain

Published, JLR Papers in Press, July 3, 2007.

¹ To whom correspondence should be addressed. e-mail: 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 the phosphorylation of protein kinase B (PKB) and extracellularly regulated kinases 1/2 (ERK 1/2), which is an indication of their activation, in these cells. These effects are probably mediated through the interaction of S1P with the Gi protein-coupled receptors S1P1/3, as pretreatment with pertussis toxin or with the S1P1/3 antagonist VPC 23019 completely abolished the phosphorylation of these kinases. Inhibitors of phosphatidylinositol 3-kinase (PI3K) or mitogen-activated protein 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 pretreated with LY 294002 and PD 98059 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 the stimulation of PLD and aldosterone secretion.

Supplementary key words adrenal gland • ceramide • mitogen-activated protein kinase • glomerulosa cells • mineralocorticoids • phospholipase D • protein kinase B • sphingolipid • steroids • phosphatidylinositol 3-kinase • mitogen-activated protein kinase kinase/extracellularly regulated kinase

Abbreviations: ERK, extracellularly regulated kinase; MEK, mitogen-activated kinase kinase; PI3K, phosphatidylinositol 3-kinase; PKB, protein kinase B; PKC, protein kinase C; PLD, phospholipase D; PMA, 4ß-phorbol 12-myristate 13-acetate; PTX, pertussis toxin; S1P, sphingosine-1-phosphate; ZG, zona glomerulosa

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