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The TRPM7 channel is inactivated by PIP2 hydrolysis

Nature Cell Biology volume 4, pages 329–336 (2002)Cite this article

Abstract

TRPM7 (ChaK1, TRP-PLIK, LTRPC7) is a ubiquitous, calcium-permeant ion channel that is unique in being both an ion channel and a serine/threonine kinase. The kinase domain of TRPM7 directly associates with the C2 domain of phospholipase C (PLC). Here, we show that in native cardiac cells and heterologous expression systems, Gαq-linked receptors or tyrosine kinase receptors that activate PLC potently inhibit channel activity. Numerous experimental approaches demonstrated that phosphatidylinositol 4,5-bisphosphate (PIP2), the substrate of PLC, is a key regulator of TRPM7. We conclude that receptor-mediated activation of PLC results in the hydrolysis of localized PIP2, leading to inactivation of the TRPM7 channel.

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Figure 1: TRPM7 conductance is inhibited by CCh stimulation of the M1 receptor.
Figure 2: Concurrent activation of PIP2 hydrolysis and inhibition of channel activity by CCh.
Figure 3: The kinase domain of TRPM7 interacts with the C2 domain of PLC.
Figure 4: PKC and DAG do not affect ITRPM7.
Figure 5: PIP2 speeds channel recovery.
Figure 6: PIP2 regulates single-channel activity.
Figure 7: Oleoyl-LPA inhibits a TRPM7-like current in ventricular fibroblasts.
Figure 8: A model of TRPM7 regulation by PIP2 and PLC.

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Acknowledgements

We thank S. Goo Rhee for PLC-β4 and PLC-γ1 cDNAs, M. Rebecchi for expression plasmids containing PLC-δ1 and the PH domain of PLC-δ1, and E. Oancea for the C12–GFP and GFP-tagged PLC-δ1 expression constructs. We also thank Q. Shi for her technical advice in culturing ventricular fibroblasts and L. Cantley, C. Carpenter, A. Morris and S. McLaughlin for helpful discussions. L.Y. was supported by the Heart and Stroke Foundation of Canada.

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  1. Loren W. Runnels and Lixia Yue: The first two authors contributed equally to the work.

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  1. Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School, Enders 1309, 320 Longwood Avenue, Boston, 02115, MA, USA

    Loren W. Runnels, Lixia Yue & David E. Clapham

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Runnels, L., Yue, L. & Clapham, D. The TRPM7 channel is inactivated by PIP2 hydrolysis. Nat Cell Biol 4, 329–336 (2002). https://doi.org/10.1038/ncb781

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