Sphingosine kinase-mediated calcium signaling by muscarinic acetylcholine receptors

Citation
Cj. Van Koppen et al., Sphingosine kinase-mediated calcium signaling by muscarinic acetylcholine receptors, LIFE SCI, 68(22-23), 2001, pp. 2535-2540
Citations number
11
Categorie Soggetti
Biochemistry & Biophysics
Journal title
LIFE SCIENCES
ISSN journal
00243205 → ACNP
Volume
68
Issue
22-23
Year of publication
2001
Pages
2535 - 2540
Database
ISI
SICI code
0024-3205(20010427)68:22-23<2535:SKCSBM>2.0.ZU;2-6
Abstract
Based on the finding that G protein-coupled receptors (GPCRs) can induce Ca 2+ mobilization, apparently independent of the phospholipase C (Pl,C)/inosi tol-1,4,5-trisphosphate (IP3) pathway, we investigated whether sphingosine kinase, which generates sphingosine-l-phosphate (SPP), is involved in calci um signaling by mAChR and other GPCRs. Inhibition of sphingosine kinase by DL-threo-dihydrosphingosine and N,N-dimethylsphingosine markedly inhibited [Ca2+](i) increases elicited by M-2 and M-3 mAChRs in HEK-293 cells without affecting PLC activation. Activation of M-2 and M-3 mAChR rapidly and tran siently stimulated production of SPP. Furthermore, microinjection of SPP in to HEK-293 cells induced rapid and transient Ca2+ mobilization. Pretreatmen t of HEK-293 cells with the calcium chelator BAPTA/AM fully blocked mAChR-i nduced SPP production. On the other hand, incubation of HEK-293 cells with calcium ionophores activated SPP production. Similar findings were obtained for formyl peptide and P2Y(2) purinergic receptors in HL-60 cells. On the basis of these studies we propose, that following initial IP3 production by receptor-mediated PLC activation, a local discrete increase in [Ca2+](i) i nduces sphingosine kinase stimulation, which ultimately leads to full calci um mobilization. Thus, sphingosine kinase activation most likely represents an amplification system for calcium signaling by mAChRs and other GPCRs. ( C) 2001 Elsevier Science Inc. AH rights reserved.