Diacylglycerol mediates the T-cell receptor-driven Ca(2+) influx in T cells by a novel mechanism independent of protein kinase C activation.
The mechanism of Ca(2+) influx in nonexcitable cells is not known yet. According to the capacitative hypothesis, Ca(2+) influx is triggered by IP(3)-mediated Ca(2+) release from the intracellular Ca(2+) stores. Conversely, many workers have reported a lack of association between release and influx. In this work, the role of diacylglycerol (DAG) as the mediator of T-cell receptor (TCR)-driven Ca(2+) influx in T cells was investigated. Stimulation of mouse splenic T cells with naturally occurring DAG caused Ca(2+) entry in a dose- and time-dependent manner. Such stimulation was blocked by Ni(2+), a divalent cation known to block Ca(2+) channels. Inhibition of protein kinase C (PKC) by calphostin C did not inhibit, but slightly enhanced, the DAG-stimulated Ca(2+) entry. However, inhibition of DAG metabolism by DAG kinase and lipase inhibitors enhanced the DAG-stimulated Ca(2+) entry. DAG lipase and kinase inhibitors also enhanced the Ca(2+) entry in T cells stimulated through TCR/CD3 complex with anti-CD3 antibody. Calphostin C did not affect the anti-CD3-stimulated Ca(2+) entry. These results showed that TCR-driven Ca(2+) influx in T cells is mediated by DAG through a novel mechanism(s) independent of PKC activation.
Chakrabarti
R
R
Molecular Biology Unit, Institute of Medical Sciences, Banaras Hindu University, Varanasi-221005, India. jvm@banaras.ernet.in
Kumar
S
S
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D003512:Cyclohexanones / Q000494:pharmacology; D004075:Diglycerides / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D009281:Naphthalenes / Q000494:pharmacology; D009532:Nickel / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology
D003512:Cyclohexanones; D004075:Diglycerides; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D011744:Pyrimidinones; D011948:Receptors, Antigen, T-Cell; D013844:Thiazoles; D009532:Nickel; C036535:1,6-bis(cyclohexyloximinocarbonyl)hexane; C047505:R 59022; D011493:Protein Kinase C; D008071:Lipoprotein Lipase; C058819:calphostin C