Effect of sphingosine-1-phosphate on L-type calcium current and Ca2+ 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.

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“…A further study demonstrated that S1P could inhibit I CaL in SAN cells under adrenergic tone . This was recently corroborated by a study from Egom et al that has shown that in rat ventricular myocytes, S1P does not affect basal activity of I CaL , but is able to partially reverse the I CaL ‐increasing effect of the beta adrenergic agonist isoproterenol. This effect is thought to be mediated, at least in part, via the Pak1‐PP2A signaling pathway.…”

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“…Calcium metabolism is crucial for myocardial contractility and modulates heart pump function [94]. S1P regulates calcium metabolism in cardiomyocytes [39,95] and the ionic status in cells of the sinoatrial node, which reduces heart rate [39,96], and has conceivably been reported to promote ventricular contraction and blood pressure [39].…”

The p21‐activated kinase 1 (Pak1) signalling pathway in cardiac disease: from mechanistic study to therapeutic exploration

“…S1P alleviated the increase in I CaL amplitude and spontaneous Ca 2+ waves induced by isoprenaline in rat ventricular myocytes. This study also showed increased co‐localization of Pak1 and PP2A, suggesting that S1P blunted the effects evoked by stimulation of the β‐adrenoceptors via the Pak1–PP2A interaction (Egom et al , ). Numerous studies have suggested that S1P can modulate intracellular Ca 2+ levels in myocytes (Guo et al , ), without affecting the basal activity of L‐type Ca 2+ channels (Nakajima et al , ).…”

“…Sphingosine ‐1‐phosphate (S1P, a circulating bioactive sphingolipid) was found to regulate intracellular Ca 2+ handling by L‐type Ca 2+ channels through the Pak1–PP2A‐mediated signalling pathway (Egom et al , ). S1P alleviated the increase in I CaL amplitude and spontaneous Ca 2+ waves induced by isoprenaline in rat ventricular myocytes.…”