Sphingosine (Sph) has been implicated as a modulator of membrane signal transduction systems and as a regulatory element of cardiac and skeletal muscle physiology, but little information is presently available on its precise mechanism of action. Recent studies have shown that sphingosine 1-phosphate (S1P), generated by the action of sphingosine kinase (SphK) on Sph, also possesses biological activity, acting as an intracellular messenger, as well as an extracellular ligand for specific membrane receptors. At present, however, it is not clear whether the biological effects elicited by Sph are attributable to its conversion into S1P. In the present study, we show that Sph significantly stimulated phospholipase D (PLD) activity in mouse C2C12 myoblasts via a previously unrecognized mechanism that requires the conversion of Sph into S1P and its subsequent action as extracellular ligand. Indeed, Sph-induced activation of PLD was inhibited by N,N-dimethyl-D-erythro-sphingosine (DMS), at concentrations capable of specifically inhibiting SphK. Moreover, the crucial role of SphK-derived S1P in the activation of PLD by Sph was confirmed by the observed potentiated effect of Sph in myoblasts where SphK1 was overexpressed, and the attenuated response in cells transfected with the dominant negative form of SphK1. Notably, the measurement of S1P formation in vivo by employing labelled ATP revealed that cell-associated SphK activity in the extracellular compartment largely contributed to the transformation of Sph into S1P, with the amount of SphK released into the medium being negligible. It will be important to establish whether the mechanism of action identified in the present study is implicated in the multiple biological effects elicited by Sph in muscle cells.
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Research Article|
July 27 2004
Sphingosine kinase activity is required for sphingosine-mediated phospholipase D activation in C2C12 myoblasts
Elisabetta MEACCI;
Elisabetta MEACCI
*Dipartimento di Scienze Biochimiche, Università degli Studi di Firenze, Viale G.B.Morgagni 50, 50134 Florence, Italy
†Istituto Interuniversitario di Miologia (IIM), Università degli Studi di Firenze, Viale G.B.Morgagni 50, 50134 Florence, Italy
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Francesca CENCETTI;
Francesca CENCETTI
*Dipartimento di Scienze Biochimiche, Università degli Studi di Firenze, Viale G.B.Morgagni 50, 50134 Florence, Italy
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Chiara DONATI;
Chiara DONATI
*Dipartimento di Scienze Biochimiche, Università degli Studi di Firenze, Viale G.B.Morgagni 50, 50134 Florence, Italy
†Istituto Interuniversitario di Miologia (IIM), Università degli Studi di Firenze, Viale G.B.Morgagni 50, 50134 Florence, Italy
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Francesca NUTI;
Francesca NUTI
*Dipartimento di Scienze Biochimiche, Università degli Studi di Firenze, Viale G.B.Morgagni 50, 50134 Florence, Italy
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Laura BECCIOLINI;
Laura BECCIOLINI
*Dipartimento di Scienze Biochimiche, Università degli Studi di Firenze, Viale G.B.Morgagni 50, 50134 Florence, Italy
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Paola BRUNI
Paola BRUNI
1
*Dipartimento di Scienze Biochimiche, Università degli Studi di Firenze, Viale G.B.Morgagni 50, 50134 Florence, Italy
†Istituto Interuniversitario di Miologia (IIM), Università degli Studi di Firenze, Viale G.B.Morgagni 50, 50134 Florence, Italy
1To whom correspondence should be addressed (e-mail paola.bruni@unifi.it).
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Publisher: Portland Press Ltd
Received:
October 27 2003
Revision Received:
April 22 2004
Accepted:
April 27 2004
Accepted Manuscript online:
April 27 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2004
Biochem J (2004) 381 (3): 655–663.
Article history
Received:
October 27 2003
Revision Received:
April 22 2004
Accepted:
April 27 2004
Accepted Manuscript online:
April 27 2004
Citation
Elisabetta MEACCI, Francesca CENCETTI, Chiara DONATI, Francesca NUTI, Laura BECCIOLINI, Paola BRUNI; Sphingosine kinase activity is required for sphingosine-mediated phospholipase D activation in C2C12 myoblasts. Biochem J 1 August 2004; 381 (3): 655–663. doi: https://doi.org/10.1042/BJ20031636
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