Abstract
Activation of IK(ACh) is the major effect of the vagal neutrotransmitter
acetylcholine in the heart. We report that both lysosphingomyelin
(D-erythro-sphingosyl-phosphorylcholine; SPC) and sphingosine 1-phosphate
(SPP) activate IK(ACh) in guinea pig atrial myocytes through the
same receptor with an EC50 of 1.5 and 1.2 nM, respectively. Pertussis
toxin abolished the activation of IK(ACh) by either lipid. The putative
receptor showed an exquisite stereoselectivity for the naturally
occurring D-erythro-(2S,3R)-SPC stereoisomer, the structure of which
was confirmed by mass spectroscopy and NMR. These lipids caused complete
homologous and heterologous desensitization with each other but not
with ACh, indicating that both act on the same receptor. This receptor
displays a distinct structure-activity relationship: it requires
an unsubstituted amino group because N-acetyl-SPC, lysophosphatidic
acid and lysophosphatidylcholine were inactive. Because SPP and SPC
are naturally occurring products of membrane lipid metabolism, it
appears that these compounds might be important extracellular mediators
acting on a family of bona fide G protein-coupled receptors. Expression
of these receptors in the heart raises the possibility that sphingolipids
may be a part of the physiological and/or pathophysiological regulation
of the heart. Based on their ligand selectivity we propose a classification
of the sphingolipid receptors.
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