title: Effect of sphingosine-1-phosphate on L-type calcium current and Ca(2+) transient in rat ventricular myocytes.
abstract: Modulation of Ca(2+) homoeostasis in cardiac myocytes plays a major role in beat-to-beat regulation of heart function. Previous studies suggest that sphingosine-1-phosphate (S1P), a biologically active sphingomyelin metabolite, regulates Ca(2+) handling in cardiac myocytes, but the underlying mechanism is unclear. In the present study, we tested the hypothesis that S1P-induced functional alteration of intracellular Ca(2+) handling includes the L-type calcium channel current (ICa,L) via a signalling pathway involving P21-activated kinase 1 (Pak1). Our results show that, in rat ventricular myocytes, S1P (100 nM) does not affect the basal activity of ICa,L but is able to partially reverse the effect of the β-adrenergic agonist Isoproterenol (ISO, 100 nM) on ICa,L. S1P (25 nM) also significantly prevents ISO (5 nM)-induced Ca(2+) waves and diastolic Ca(2+) release in these cells. Our further molecular characterisation demonstrates that Pak1 activity is increased in myocytes treated with S1P (25 nM) compared with those myocytes without treatment of S1P. By immunoprecipitation we demonstrate that Pak1 and protein phosphatase 2A (PP2A) are associated in ventricular tissue indicating their functional interaction. Thus the results indicate that S1P attenuates β-adrenergic stress-induced alteration of intracellular Ca(2+) release and L-type Ca(2+) channel current at least in part via Pak1-PP2A-mediated signalling.
authors.affiliation: Education Division, Department of Clinical Medicine, University of Dublin/Trinity College, Dublin, Ireland. egom@ectrs.ca.|Egom Clinical and Translational Research Services Ltd, Halifax, NS, B3H 4R7, Canada. egom@ectrs.ca.
authors.forename: Emmanuel Eroume-A
authors.initials: EE
authors.lastname: Egom
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: James S H
authors.initials: JS
authors.lastname: Bae
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Capel
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Richards
authors.affiliation: Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, USA.
authors.forename: Yunbo
authors.initials: Y
authors.lastname: Ke
authors.affiliation: Heart Efficiency Unit, Cardiology Department, The Adelaide and Meath Hospital, Tallaght, Dublin, Ireland.
authors.forename: Rebabonye B
authors.initials: RB
authors.lastname: Pharithi
authors.affiliation: Heart Efficiency Unit, Cardiology Department, The Adelaide and Meath Hospital, Tallaght, Dublin, Ireland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Maher
authors.affiliation: Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho tr 1946/1, 656 91, Brno, Czech Republic. kruzliakpeter@gmail.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Kruzliak
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK. ming.lei@pharm.ox.ac.uk.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D006352:Heart Ventricles / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051381:Rats; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D020746:Calcium Channels, L-Type; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids; C430457:PAK1IP1 protein, human; C060506:sphingosine 1-phosphate; C514014:Ppp2ca protein, rat; D054648:Protein Phosphatase 2; D013110:Sphingosine; D002118:Calcium
keywords: L-type calcium current, ICa,L; P21-activated kinase 1, Pak1; Sphingosine-1-phosphate, S1P