M. Bunemann et al., A NOVEL MEMBRANE-RECEPTOR WITH HIGH-AFFINITY FOR LYSOSPHINGOMYELIN AND SPHINGOSINE 1-PHOSPHATE IN ATRIAL MYOCYTES, EMBO journal, 15(20), 1996, pp. 5527-5534
Activation of I-K(ACh) is the major effect of the vagal neurotransmitt
er acetylcholine in the heart, We report that both lysosphingomyelin (
D-erythro-sphingosyl-phosphorylcholine; SPC) and sphingosine 1-phospha
te (SPP) activate I-K(ACh) in guinea pig atrial myocytes through the s
ame receptor with an EC(50) of 1.5 and 1.2 nM, respectively. Pertussis
toxin abolished the activation of I-K(ACh) by either lipid, The putat
ive receptor showed an exquisite stereoselectivity for the naturally o
ccurring D-erythro-(2S,3R)-SPC stereoisomer, the structure of which wa
s confirmed by mass spectroscopy and NMR, These lipids caused complete
homologous and heterologous desensitization with each other but not w
ith ACh, indicating that both act on the same receptor. This receptor
displays a distinct structure-activity relationship: it requires an un
substituted amino group because N-acetyl-SPC, lysophosphatidic acid an
d lysophosphatidylcholine were inactive, Because SPP and SPC are natur
ally 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 b
e a part of the physiological and/or pathophysiological regulation of
the heart. Based on their ligand selectivity we propose a classificati
on of the sphingolipid receptors.