Inhibition of Ca super(2+) signalling by the sphingosine 1-phosphate receptor S1P sub(1)

• Published in: Cellular signalling Vol. 15; no. 7; pp. 677 - 687
• Main Authors: Heringdorf, DMz, Vincent, MEM, Lipinski, M, Danneberg, K, Stropp, U, Wang, D-a, Tigyi, G, Jakobs, KH
• Format: Journal Article
• Language: English
• Published: 01-07-2003
• ISSN: 0898-6568
• DOI: 10.1016/S0898-6568(03)00011-1

The lysophospholipid, sphingosine 1-phosphate (S1P), regulates a multitude of cellular functions by activating specific G protein-coupled receptors (GPCRs) (S1P sub(1-5), plus three newly identified S1P receptors). The G sub(i)-coupled S1P sub(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 sub(1) inhibits Ca super(2+) signalling in a number of cell types. In HEK-293 cells, which endogenously express S1P sub(1-3), overexpression of S1P sub(1) reduced intracellular free Ca super(2+) concentration ([Ca super(2+)] sub(i)) increases induced by various receptor agonists as well as thapsigargin. The inhibitory Ca super(2+) signalling of S1P sub(1) was blocked by pertussis toxin (PTX) and the protein kinase C (PKC) inhibitor, Goe6976, and imitated by phorbol ester and overexpression of classical PKC isoforms. Activation of S1P sub(1) stably expressed in RH7777 cells, which endogenously do not express S1P receptors, also inhibited Ca super(2+) signalling, without mediating Ca super(2+) mobilization on its own. It is concluded that the widely expressed S1P receptor S1P sub(1) inhibits Ca super(2+) signalling, most likely via G sub(i) proteins and classical PKC isoforms. Co-expression of S1P sub(1) with S1P sub(3), but not S1P sub(2), reversed the inhibitory effect of S1P sub(1), furthermore suggesting a specific interplay of S1P receptor subtypes usually found within a single cell type.