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Sphingosine-1-phosphate and the immunosuppressant, FTY720-phosphate, regulate detrusor muscle tone

Kenneth R. Watterson, Krystina M. Berg, Dmitri Kapitonov, Shawn G. Payne, Amy S. Miner, Robert Bittman, Sheldon Milstien, Paul H. Ratz¹ and Sarah Spiegel^1,2

Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA;
National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA; and

Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing, New York, USA

²Correspondence: Department of Biochemistry and Molecular Biology, VCU School of Medicine, 1101 E. Marshall St., 2011 Sanger Hall, Richmond, VA 23298, USA. E-mail: sspiegel{at}vcu.edu

Overactive bladder syndrome (OBS) results from disturbances of bladder function. Bladder smooth muscle (detrusor) exhibits spontaneous rhythmic activity (tone) independent of neurogenic control, which is enhanced in patients with OBS. We have now uncovered a prominent role for the bioactive sphingolipid metabolite, sphingosine-1-phosphate (S1P), in regulating rabbit detrusor smooth muscle tone and contraction. S1P-induced contraction of detrusor muscle was dependent on stretch and intracellular calcium. Although detrusor expresses the S1P receptors S1P₁ and S1P₂, only S1P₂ appeared to be involved in S1P-induced contraction, since SEW2871 (S1P₁ agonist) and dihydro-S1P (potent agonist for all S1P receptors except S1P₂) were poor contractile agents. In agreement, the S1P₂ antagonist JTE013 inhibited S1P-induced contraction. The fast, transient muscle contraction (phasic) mediated by S1P was dependent on phospholipase C (PLC) whereas the slower, sustained contraction (tonic) was not. Surprisingly, the immunosuppressant FTY720-phosphate, an agonist for all S1P receptors except S1P2, had distinct contractile properties and also induced slow, sustained contraction. Thus, FTY720-phosphate and/or S1P may regulate calcium channels in an S1P receptor-independent manner. Collectively, our results demonstrate that S1P may regulate detrusor smooth muscle tone and suggest that dysregulation of complex S1P signaling might contribute to OBS.—Watterson, K. R., Berg, K. M., Kapitonov, D., Payne, S. G., Miner, A. S., Bittman, R., Milstien, S., Ratz, P. H., Spiegel, S. Sphingosine-1-phosphate and the immunosuppressant, fty720-phosphate, regulate detrusor muscle tone.

Key Words: sphingolipid metabolite • calcium channels