Blood plasma and serum contain factors that activate inwardly rectifying GIRK1/GIRK4 K+ channels in atrial myocytes via one or more non-atropine-sensitive receptors coupled to pertussis-toxin-sensitive G-proteins. This channel is also the target of muscarinic M2 receptors activated by the physiological release of acetylcholine from parasympathetic nerve endings. By using a combination of HPLC and TLC techniques with matrix-assisted laser desorption ionization–time-of-flight MS, we purified and identified sphingosine 1-phosphate (SPP) and sphingosylphosphocholine (SPC) as the plasma and serum factors responsible for activating the inwardly rectifying K+ channel (IK). With the use of MS the concentration of SPC was estimated at 50nM in plasma and 130nM in serum; those concentrations exceeded the 1.5nM EC50 measured in guinea-pig atrial myocytes. With the use of reverse-transcriptase-mediated PCR and/or Western blot analysis, we detected Edg1, Edg3, Edg5 and Edg8 as well as OGR1 sphingolipid receptor transcripts and/or proteins. In perfused guinea-pig hearts, SPC exerted a negative chronotropic effect with a threshold concentration of 1µM. SPC was completely removed after perfusion through the coronary circulation at a concentration of 10µM. On the basis of their constitutive presence in plasma, the expression of specific receptors, and a mechanism of ligand inactivation, we propose that SPP and SPC might have a physiologically relevant role in the regulation of the heart.
Sphingosylphosphocholine is a naturally occurring lipid mediator in blood plasma: a possible role in regulating cardiac function via sphingolipid receptors
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Károly LILIOM, Guoping SUN, Moritz BÜNEMANN, Tamás VIRÁG, Nóra NUSSER, Daniel L. BAKER, De-an WANG, Matthew J. FABIAN, Bodo BRANDTS, Kirsten BENDER, Andreas EICKEL, Kafait U. MALIK, Duane D. MILLER, Dominic M. DESIDERIO, Gábor TIGYI, Lutz POTT; Sphingosylphosphocholine is a naturally occurring lipid mediator in blood plasma: a possible role in regulating cardiac function via sphingolipid receptors. Biochem J 1 April 2001; 355 (1): 189–197. doi: https://doi.org/10.1042/bj3550189
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