Ca2+ and voltage dependence of cardiac ryanodine receptor channel block by sphingosylphosphorylcholine

The effect of sphingosylphosphorylcholine (SPC) on the cytoplasmic Ca(2+) and voltage dependence of channel gating by cardiac ryanodine receptors (RyR) was examined in lipid bilayer experiments. Micromolar concentrations of the lysosphingolipid SPC added to cis solutions rapidly and reversibly decre...

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Bibliographic Details
Published in:Pflügers Archiv 2003-03, Vol.445 (6), p.665-673
Main Authors: Yasukochi, Midori, Uehara, Akira, Kobayashi, Sei, Berlin, Joshua R
Format: Article
Language:English
Subjects:
Animals
Calcium - metabolism
Heart - physiology
Ion Channel Gating - drug effects
Kinetics
Lipid Bilayers - metabolism
Membrane Potentials - drug effects
Myocardium - metabolism
Phosphorylcholine - analogs & derivatives
Phosphorylcholine - pharmacology
Rabbits
Ryanodine Receptor Calcium Release Channel - metabolism
Sphingosine - analogs & derivatives
Sphingosine - pharmacology
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Summary:The effect of sphingosylphosphorylcholine (SPC) on the cytoplasmic Ca(2+) and voltage dependence of channel gating by cardiac ryanodine receptors (RyR) was examined in lipid bilayer experiments. Micromolar concentrations of the lysosphingolipid SPC added to cis solutions rapidly and reversibly decreased the single-channel open probability (P(o)) of reconstituted RyR channels. The SPC-induced decrease in P(o) was marked by an increase in mean closed time and burst-like channel gating. Gating kinetics during intraburst periods were unchanged from those observed in the absence of the sphingolipid, although SPC induced a long-lived closed state that appeared to explain the observed decrease in channel P(o). SPC effects were observed over a broad range of cis [Ca(2+)] but were not competitive with Ca(2+). Interestingly, the sphingolipid-induced, long-lived closed state displayed voltage-dependent kinetics, even though other channel gating kinetics were not sensitive to voltage. Assuming SPC effects represent channel blockade, these results suggest that the blocking rate is independent of voltage whereas the unblocking rate is voltage dependent. Together, these results suggest that SPC binds directly to the cytoplasmic side of the RyR protein in a location in or near the membrane dielectric, but distinct from cytoplasmic Ca(2+) binding sites on the protein.
ISSN:0031-6768
1432-2013
DOI:10.1007/s00424-002-0945-3