Journal
FASEB JOURNAL
Volume 21, Issue 11, Pages 2818-2828Publisher
WILEY
DOI: 10.1096/fj.06-7326com
Keywords
sphingolipid metabolite; calcium channels
Categories
Funding
- Intramural NIH HHS Funding Source: Medline
- NIDDK NIH HHS [R01DK059620] Funding Source: Medline
- NIGMS NIH HHS [R37 GM043880] Funding Source: Medline
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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 S1Pinduced 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 FTY720phosphate, 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.
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