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Effect of sphingosine-1-phosphate on L-type calcium current and Ca2+ transient in rat ventricular myocytes

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Abstract

Modulation of Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ waves and diastolic Ca2+ 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 Ca2+ release and L-type Ca2+ channel current at least in part via Pak1–PP2A-mediated signalling.

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Acknowledgement

The work was supported by the Medical Research Council (G10002647: Dr Lei), the British Heart Foundation (PG11/59/29006, PG/12/21/29473: Dr. Lei).

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Authors and Affiliations

  1. Education Division, Department of Clinical Medicine, University of Dublin/Trinity College, Dublin, Ireland

    Emmanuel Eroume-A Egom

  2. Egom Clinical and Translational Research Services Ltd, Halifax, NS, B3H 4R7, Canada

    Emmanuel Eroume-A Egom

  3. Department of Pharmacology, University of Oxford, Oxford, UK

    James S.H. Bae, Rebecca Capel & Ming Lei

  4. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK

    Mark Richards

  5. Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, USA

    Yunbo Ke

  6. Heart Efficiency Unit, Cardiology Department, The Adelaide and Meath Hospital, Tallaght, Dublin, Ireland

    Rebabonye B. Pharithi & Vincent Maher

  7. Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho tr 1946/1, 656 91, Brno, Czech Republic

    Peter Kruzliak

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  1. Emmanuel Eroume-A Egom
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Correspondence to Emmanuel Eroume-A Egom, Peter Kruzliak or Ming Lei.

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Egom, E.EA., Bae, J.S., Capel, R. et al. Effect of sphingosine-1-phosphate on L-type calcium current and Ca2+ transient in rat ventricular myocytes. Mol Cell Biochem 419, 83–92 (2016). https://doi.org/10.1007/s11010-016-2752-8

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  • DOI: https://doi.org/10.1007/s11010-016-2752-8

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