Sphingosine 1-phosphate: a novel stimulator of aldosterone secretion.
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 alpha and delta and extracellular Ca2+, and it was inhibited by pertussis toxin (PTX). S1P activated phospholipase D (PLD) through a PTX-sensitive mechanism, also involving PKC alpha and delta 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 alpha and delta are all important components in the cascade of events controlling this process.
Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country, 48080 Bilbao, Spain.
Leyre
L
Brizuela
Miriam
M
Rábano
Ana
A
Peña
Patricia
P
Gangoiti
José María
JM
Macarulla
Miguel
M
Trueba
Antonio
A
Gómez-Muñoz
D000450:Aldosterone / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology; D002746:Chlorpromazine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D037342:Pertussis Toxin / Q000378:metabolism / Q000494:pharmacology; D010711:Phosphatidate Phosphatase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010739:Phospholipase D / Q000187:drug effects / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D015384:Zona Glomerulosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D002518:Ceramides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008246:Lysophospholipids; C101954:N-caproylsphingosine; D000804:Angiotensin II; C060506:sphingosine 1-phosphate; D000450:Aldosterone; D011433:Propranolol; D037342:Pertussis Toxin; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D010711:Phosphatidate Phosphatase; D010739:Phospholipase D; D013110:Sphingosine; D002118:Calcium; D002746:Chlorpromazine