Sci Rep. 2011;1:146. doi: 10.1038/srep00146. Epub 2011 Nov 9.

Phosphatidylinositol 4,5-bisphosphate (PIP(2)) controls magnesium gatekeeper TRPM6 activity.External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c

Xie, J., Sun, B., Du, J., Yang, W., Chen, H. C., Overton, J. D., Runnels, L. W., Yue, L.,
["Calhoun Cardiology Center, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA.,"]
TRPM6 is crucial for human Mg2+ homeostasis as patients carrying TRPM6 mutations develop hypomagnesemia and secondary hypocalcemia (HSH). However, the activation mechanism of TRPM6 has remained unknown. Here we demonstrate that phosphatidylinositol-4,5-bisphophate (PIP2) controls TRPM6 activation and Mg2+ influx. Stimulation of PLC-coupled M1-receptors to deplete PIP2 potently inactivates TRPM6. Translocation of over-expressed 5-phosphatase to cell membrane to specifically hydrolyze PIP2 also completely inhibits TRPM6. Moreover, depolarization-induced-activation of the voltage-sensitive-phosphatase (Ci-VSP) simultaneously depletes PIP2 and inhibits TRPM6. PLC-activation induced PIP2-depletion not only inhibits TRPM6, but also abolishes TRPM6-mediated Mg2+ influx.Furthermore, neutralization of basic residues in the TRP domain leads to nonfunctional or dysfunctional mutants with reduced activity by PIP2, suggesting that they are likely to participate in interactions with PIP2.Our data indicate that PIP2 is required for TRPM6 channel function; hydrolysis of PIP2 by PLC-coupled hormones/agonists may constitute an important pathway for TRPM6 gating, and perhaps Mg2+ homeostasis.
PMID: 22180838External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c
Screening Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Experimental screening Non-experimental screening Reference
TRP channel construct Interactor source
TRP channel Interactor Method Species Region Species Organ/tissue Sample type
TRPM6 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 PLCƢ1 Inference Prediction 22180838
TRPM6 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 PLCƢ2 Inference Prediction 22180838
TRPM6 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 PLCƢ3 Inference Prediction 22180838
TRPM7 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 PLCƤ1 Inference Prediction 22180838
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
Validation: In vitro validation Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
  Assay with recombinant proteins Reference
TRP channel construct Interactor construct
TRP channel Interactor Method Species Region Expression system Species Region Expression system
TRPM6 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 PLCƢ1 Fusion protein-pull down assay Not specified Kinase domain E. coli Not specified Full-length HEK293 lysates 22180838
TRPM6 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 PLCƢ2 Fusion protein-pull down assay Not specified Kinase domain E. coli Not specified Full-length HEK293 lysates 22180838
TRPM6 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 PLCƢ3 Fusion protein-pull down assay Not specified Kinase domain E. coli Not specified Full-length HEK293 lysates 22180838
TRPM7 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 PLCƢ1 Fusion protein-pull down assay Not specified Kinase domain E. coli Not specified Full-length HEK293 lysates 22180838
TRPM7 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 PLCƢ2 Fusion protein-pull down assay Not specified Kinase domain E. coli Not specified Full-length HEK293 lysates 22180838
TRPM7 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 PLCƢ3 Fusion protein-pull down assay Not specified Kinase domain E. coli Not specified Full-length HEK293 lysates 22180838
TRPM7 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 PLCƤ1 Fusion protein-pull down assay Not specified Kinase domain E. coli Not specified Full-length HEK293 lysates 22180838
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
TRP / Interactor

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