Originally published In Press as doi:10.1074/jbc.M505842200 on June 22, 2005
J. Biol. Chem., Vol. 280, Issue 33, 29559-29569, August 19, 2005
Endogenous TRPC1, TRPC3, and TRPC7 Proteins Combine to Form Native Store-operated Channels in HEK-293 Cells*
Tatiana K. Zagranichnaya,
Xiaoyan Wu, and
Mitchel L. Villereal
From the
Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, Illinois 60637
Endogenously expressed canonical transient receptor potential (TRPC) homologs were investigated for their role in forming store-operated, 1-oleoyl-2-acetyl-sn-glycerol-stimulated, or carbachol (CCh)-stimulated calcium entry pathways in HEK-293 cells. Measurement of thapsigargin-stimulated Ba2+ entry indicated that the individual suppression of TRPC1, TRPC3, or TRPC7 protein levels, by small interfering RNA (siRNA) techniques, dramatically inhibited (52–68%) store-operated calcium entry (SOCE), whereas suppression of TRPC4 or TRPC6 had no effect. Combined suppression of TRPC1-TRPC3, TRPC1-TRPC7, TRPC3-TRPC7, or TRPC1-TRPC3-TRPC7 gave only slightly more inhibition of SOCE (74–78%) than seen with suppression of TRPC1 alone (68%), suggesting that these three TRPC homologs work in tandem to mediate a large component of SOCE. Evidence from co-immunoprecipitation experiments indicates that a TRPC1-TRPC3-TRPC7 complex, predicted from siRNA results, does exist. The suppression of either TRPC3 or TRPC7, but not TRPC1, induced a high Ba2+ leak flux that was inhibited by 2-APB and SKF96365 suggesting that the influx is via leaky store-operated channels. The high Ba2+ leak flux is eliminated by co-suppression of TRPC1-TRPC3 or TRPC1-TRPC7. For 1-oleoyl-2-acetyl-sn-glycerol-stimulated cells, siRNA data indicate that TRPC1 plays no role in mediating Ba2+ entry, which appears to be mediated by the participation of TRPC3, TRPC4, TRPC6, and TRPC7. CCh-stimulated Ba2+ entry, on the other hand, could be inhibited by suppression of any of the five endogenously expressed TRPC homologs, with the degree of inhibition being consistent with CCh stimulation of both store-operated and receptor-operated channels. In summary, endogenous TRPC1, TRPC3, and TRPC7 participate in forming heteromeric store-operated channels, whereas TRPC3 and TRPC7 can also participate in forming heteromeric receptor-operated channels.
Received for publication, May 31, 2005
, and in revised form, June 21, 2005.
Note Added in Proof—A recent paper demonstrated that antisense to TRPC1 and antisense to TRPC3 attenuate thapsigargin- and OAG-stimulated Ca2+ entry in HSY cells and that TRPC1 and TRPC3 co-immunoprecipitate (53).
* This work was supported by NIGMS, National Institutes of Health, Grant GM54500 (to M. L. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains one additional table.
To whom correspondence should be addressed: Neurobiology, Pharmacology, and Physiology, University of Chicago, 947 E. 58th St., Chicago, IL 60637. Tel.: 773-702-9334; Fax: 773-702-3774; E-mail: mitch{at}bsd.uchicago.edu.
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Copyright © 2005 by the American Society for Biochemistry and Molecular Biology.
