Complex regulation of the TRPC3, 6 and 7 channel subfamily by diacylglycerol and phosphatidylinositol-4,5-bisphosphate
Section snippets
Methods
Experiments were carried out with HEK293 cells stably expressing either TRPC3, TRPC6 or TRPC7 [9], [10], [11]. Ca2+ measurements were carried out with TRPC7-expressing cells loaded with Fura-2-AM and a cell imaging system (Intracellular Imaging, Inc., Cincinnati, OH) as described previously [12]. For Fura-2 measurements, the ratio obtained by dividing the emitted fluorescence from excitation at 340 nm by the emitted fluorescence measured after excitation at 380 nm is reported as an indicator of
Results
As previously demonstrated [15], [16], in HEK293 cells stably expressing TRPC7, application of the membrane permeant diacylglycerol analog, oleyl-acetyl glycerol (OAG) activated Ca2+ entry (Fig. 1A). Pretreatment of the cells with the phosphoinositide lipid kinase inhibitor, LY294002 [17], [18] caused near total inhibition of the [Ca2+]i signal (Fig. 1A). This inhibition does not likely result from a direct action on TRPC7 channels, because addition of LY294002 after the Ca2+ signal had
Discussion
A wide variety of ion channels and plasma membrane transporters are known to be regulated by the acidic phospholipid, PIP2 [7], [8]. Generally, this modulation is a positive one. Since PIP2 is constitutively present in the membrane of cells and can be decreased by activation of PLC-coupled receptors, this may provide a means for negative regulation of ion channel signaling pathways. That appears to be the case for a number of channels in the TRP superfamily that are activated by PIP2 and
Acknowledgements
Drs. David Armstrong, Jerrel Yakel and Guillermo Vazquez read the manuscript and provided helpful comments. This work was supported by funds from the Intramural Program of the NIEHS and NIH.
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- 1
Present address: Inserm U800, Universite de Lille 1, Villeneuve d’Ascq F-59650, France.
- 2
Present address: Center for Cardiovascular Sciences, Albany Medical Center, 47 New Scotland Avenue, Albany, New York 12208, United States.
- 3
These authors contributed equally to this work.