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Sphingosine‐1‐phosphate and the immunosuppressant, FTY720‐phosphate, regulate detrusor muscle tone
Author(s) -
Watterson Kenneth R.,
Berg Krystina M.,
Kapitonov Dmitri,
Payne Shawn G.,
Miner Amy S.,
Bittman Robert,
Milstien Sheldon,
Ratz Paul H.,
Spiegel Sarah
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-7326com
Subject(s) - detrusor muscle , agonist , contraction (grammar) , muscle contraction , sphingosine 1 phosphate , receptor , endocrinology , chemistry , overactive bladder , medicine , sphingosine 1 phosphate receptor , phospholipase c , calcium in biology , sphingosine , urinary bladder , biology , pathology , alternative medicine
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 sphingo‐lipid metabolite, sphingosine‐1‐phosphate (S1P), in regulating rabbit detrusor smooth muscle tone and con‐traction. S1P‐induced contraction of detrusor muscle was dependent on stretch and intracellular calcium. Although detrusor expresses the S1P receptors S1P 1 and S1P 2 , only S1P 2 appeared to be involved in S1P‐induced contraction, since SEW2871 (S1P 1 agonist) and dihydro‐S1P (potent agonist for all S1P receptors except S1P 2 ) were poor contractile agents. In agreement, the S1P 2 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‐phos‐phate 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 immuno‐suppressant, fty720‐phosphate, regulate detrusor muscle tone. FASEB J. 21, 2818–2828 (2007)