Abstract
1. Activation of muscarinic K+ current (IK(ACh)) by sphingosine-1-phosphate
(Sph-1-P) was studied in isolated cultured guinea-pig atrial myocytes
using whole-cell voltage clamp. 2. Sph-1-P caused activation of IK(ACh)
with an EC50 of 1.2 nM. The maximal current that could be activated
by Sph-1-P amounted to about 90% of the IK(ACh) caused by a saturating
concentration of acetylcholine (ACh, 10 microM). Sphingosine (1 microM),
which can mimic the signalling effects of Sph-1-P in other cells,
failed to cause measurable activation of IK(ACh). 3. IK(ACh) activation
by Sph-1-P was completely suppressed in cells treated with pertussis
toxin. 4. Desensitization of muscarinic receptors by pre-incubation
of the cells with carbachol did not affect the response to Sph-1-P;
likewise, pre-incubation of the cells with Sph-1-P resulted in a
reduced sensitivity to the phospholipid but not to ACh. In contrast,
pre-incubation with either Sph-1-P or a serum phospholipid previously
described as activating atrial IK(ACh) resulted in reduced sensitivity
to both phospholipids. 5. It is concluded that activation of IK(ACh)
by Sph-1-P in atrial myocytes is induced by binding to a novel G
protein-coupled phospholipid receptor.
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