title: Sphingosine-1-phosphate and the immunosuppressant, FTY720-phosphate, regulate detrusor muscle tone.
abstract: 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.
authors: Department of Biochemistry and Molecular Biology, VCU School of Medicine, 1101 E. Marshall St., Richmond, VA 23298, USA.
authors: Kenneth R
authors: KR
authors: Watterson
authors: Krystina M
authors: KM
authors: Berg
authors: Dmitri
authors: D
authors: Kapitonov
authors: Shawn G
authors: SG
authors: Payne
authors: Amy S
authors: AS
authors: Miner
authors: Robert
authors: R
authors: Bittman
authors: Sheldon
authors: S
authors: Milstien
authors: Paul H
authors: PH
authors: Ratz
authors: Sarah
authors: S
authors: Spiegel
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D005260:Female; D000068876:Fingolimod Hydrochloride; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008246:Lysophospholipids / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009129:Muscle Tonus / Q000187:drug effects*; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism*; D011409:Propylene Glycols / Q000494:pharmacology*; D011817:Rabbits; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010738:Type C Phospholipases / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D010738:Type C Phospholipases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D002118:Calcium