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Journal of Lipid Research, Vol. 47, 1238-1249, June 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Sphingosine 1-phosphate: a novel stimulator of aldosterone secretion

Leyre Brizuela, Miriam Rábano, Ana Peña, Patricia Gangoiti, 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, March 22, 2006.

¹ To whom correspondence should be addressed. e-mail: antonio.gomez{at}ehu.es

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid capable of regulating critical physiological and pathological functions. Here, we report for the first time that S1P stimulates aldosterone secretion in cells of the zona glomerulosa of the adrenal gland. Regulation of aldosterone secretion is important because this hormone controls electrolyte and fluid balance and is implicated in cardiovascular homeostasis. S1P-stimulated aldosterone secretion was dependent upon the protein kinase C (PKC) isoforms and and extracellular Ca²⁺, and it was inhibited by pertussis toxin (PTX). S1P activated phospholipase D (PLD) through a PTX-sensitive mechanism, also involving PKC and and extracellular Ca²⁺. Primary alcohols, which attenuate the formation of phosphatidic acid (the product of PLD), and cell-permeable ceramides, which inhibit PLD activity, blocked S1P-stimulated aldosterone secretion. Furthermore, propranolol, chlorpromazine, and sphingosine, which are potent inhibitors of phosphatidate phosphohydrolase (PAP) (the enzyme that produces diacylglycerol from phosphatidate), also blocked aldosterone secretion. These data suggest that the PLD/PAP pathway plays a crucial role in the regulation of aldosterone secretion by S1P and that Gi protein-coupled receptors, extracellular Ca²⁺, and the PKC isoforms and are all important components in the cascade of events controlling this process.

Abbreviations: ACTH, adrenocorticotropic hormone; C₂-ceramide, N-acetylsphingosine; C₆-ceramide, N-hexanoylsphingosine; PA, phosphatidate; PAP, phosphatidate phosphohydrolase; PKC, protein kinase C; PLD, phospholipase D; PMA, 4ß-phorbol 12-myristate 13-acetate; PTX, pertussis toxin; S1P, sphingosine-1-phosphate; ZG, zona glomerulosa

Supplementary key words adrenal gland • atherosclerosis • ceramides • phospholipase D • protein kinase C • sphingolipids

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				L. Brizuela, M. Rabano, P. Gangoiti, N. Narbona, J. M. Macarulla, M. Trueba, and A. Gomez-Munoz Sphingosine-1-phosphate stimulates aldosterone secretion through a mechanism involving the PI3K/PKB and MEK/ERK 1/2 pathways J. Lipid Res., October 1, 2007; 48(10): 2264 - 2274. [Abstract] [Full Text] [PDF]