TRPC channels as STIM1-regulated store-operated channels - PubMed (original) (raw)

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TRPC channels as STIM1-regulated store-operated channels

Paul F Worley et al. Cell Calcium. 2007 Aug.

Abstract

Receptor-activated Ca(2+) influx is mediated largely by store-operated channels (SOCs). TRPC channels mediate a significant portion of the receptor-activated Ca(2+) influx. However, whether any of the TRPC channels function as a SOC remains controversial. Our understanding of the regulation of TRPC channels and their function as SOCs is being reshaped with the discovery of the role of STIM1 in the regulation of Ca(2+) influx channels. The findings that STIM1 is an ER resident Ca(2+) binding protein that regulates SOCs allow an expanded and molecular definition of SOCs. SOCs can be considered as channels that are regulated by STIM1 and require the clustering of STIM1 in response to depletion of the ER Ca(2+) stores and its translocation towards the plasma membrane. TRPC1 and other TRPC channels fulfill these criteria. STIM1 binds to TRPC1, TRPC2, TRPC4 and TRPC5 but not to TRPC3, TRPC6 and TRPC7, and STIM1 regulates TRPC1 channel activity. Structure-function analysis reveals that the C-terminus of STIM1 contains the binding and gating function of STIM1. The ERM domain of STIM1 binds to TRPC channels and a lysine-rich region participates in the gating of SOCs and TRPC1. Knock-down of STIM1 by siRNA and prevention of its translocation to the plasma membrane inhibit the activity of native SOCs and TRPC1. These findings support the conclusion that TRPC1 is a SOC. Similar studies with other TRPC channels demonstrate their regulation by STIM1 and indicate that all TRPC channels, except TRPC7, function as SOCs.

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Figures

Fig. 1

Fig. 1

Majority of the YFP-STIM1 D76A punctae are not on the plasma membrane. HEK293 cells were transfected with YFPmGluR1 together with Homer1 and Shank3 to get the YFP-mGluR1 to the plasma membrane (A, B) or YFP-STIM1 D76A (C, D). A and C are intrinsic YFP signals. B and D are images of surface live staining with an anti- GFP rabbit polyclonal antibody. The intense signal in A is from Golgi. Scale bar, 10 µm.

Fig. 2

Fig. 2

STIM1 and its domains

Fig. 3

Fig. 3

The predicted two-turn helix of the C-terminal tail of STIM1.

Fig. 4

Fig. 4. Interaction of STIM1 with TRPC channels

Panel (a) shows to co-IP of STIM1 and the indicated TRPC channels expressed in HEK cells. Panel (b) shows the pull-down of the indicated TRPC channels by GST-ERM domain of STIM1.

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