Inhibition of Ca(2+) signalling by the sphingosine 1-phosphate receptor S1P(1).
The lysophospholipid, sphingosine 1-phosphate (S1P), regulates a multitude of cellular functions by activating specific G protein-coupled receptors (GPCRs) (S1P(1-5), plus three newly identified S1P receptors). The G(i)-coupled S1P(1) receptor inhibits adenylyl cyclase, stimulates mitogen-activated protein kinases (MAP kinases) and cell migration, and is required for blood vessel maturation. Here, we report that S1P(1) inhibits Ca(2+) signalling in a number of cell types. In HEK-293 cells, which endogenously express S1P(1-3), overexpression of S1P(1) reduced intracellular free Ca(2+) concentration ([Ca(2+)](i)) increases induced by various receptor agonists as well as thapsigargin. The inhibitory Ca(2+) signalling of S1P(1) was blocked by pertussis toxin (PTX) and the protein kinase C (PKC) inhibitor, Gö6976, and imitated by phorbol ester and overexpression of classical PKC isoforms. Activation of S1P(1) stably expressed in RH7777 cells, which endogenously do not express S1P receptors, also inhibited Ca(2+) signalling, without mediating Ca(2+) mobilization on its own. It is concluded that the widely expressed S1P receptor S1P(1) inhibits Ca(2+) signalling, most likely via G(i) proteins and classical PKC isoforms. Co-expression of S1P(1) with S1P(3), but not S1P(2), reversed the inhibitory effect of S1P(1), furthermore suggesting a specific interplay of S1P receptor subtypes usually found within a single cell type.
zu Heringdorf
Dagmar Meyer
DM
Institut für Pharmakologie, Universitätsklinikum Essen, Hufelandstrasse 55, D-45122 Essen, Germany. meyer-heringdorf@uni-essen.de
Vincent
Myriam E M
ME
Lipinski
Matthias
M
Danneberg
Kerstin
K
Stropp
Udo
U
Wang
De-an
DA
Tigyi
Gabor
G
Jakobs
Karl H
KH
D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008246:Lysophospholipids; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D049312:Receptors, Lysophospholipid; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; C060506:sphingosine 1-phosphate; D011493:Protein Kinase C; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D013110:Sphingosine; D002118:Calcium