J Biol Chem. 2014 Feb 21;289(8):5217-27. doi: 10.1074/jbc.M113.512285. Epub 2014 Jan 2.
The TRPM6 kinase domain determines the Mg.ATP sensitivity of TRPM7/M6 heteromeric ion channels.
Zhang, Z., Yu, H., Huang, J., Faouzi, M., Schmitz, C., Penner, R., Fleig, A.,
["From the Laboratory of Cell and Molecular Signaling, Center for Biomedical Research, The Queen's Medical Center and John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96813 and."]
["From the Laboratory of Cell and Molecular Signaling, Center for Biomedical Research, The Queen's Medical Center and John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96813 and."]
The transient receptor potential melastatin member 7 (TRPM7) and member 6 (TRPM6) are divalent cation channel kinases essential for magnesium (Mg(2+)) homeostasis in vertebrates. It remains unclear how TRPM6 affects divalent cation transport and whether this involves functional homomeric TRPM6 plasma membrane channels or heteromeric channel assemblies with TRPM7. We show that homomeric TRPM6 is highly sensitive to intracellular free Mg(2+) and therefore unlikely to be active at physiological levels of [Mg(2+)]i. Co-expression of TRPM7 and TRPM6 produces heteromeric TRPM7/M6 channels with altered pharmacology and sensitivity to intracellular Mg.ATP compared with homomeric TRPM7. Strikingly, the activity of heteromeric TRPM7/M6 channels is independent of intracellular Mg.ATP concentrations, essentially uncoupling channel activity from cellular energy status. Disruption of TRPM6 kinase phosphorylation activity re-introduces Mg.ATP sensitivity to the heteromeric channel similar to that of TRPM7. Thus, TRPM6 modulates the functionality of TRPM7, and the TRPM6 kinase plays a critical role in tuning the phenotype of the TRPM7.M6 channel complex.
PMID: 24385424
 Screening
Validation: In vitro validation
Validation: In vivo validation
Characterization
Functional consequence
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Functional consequence
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| TRP channel | Interactor | Method | Post-translational modification | Subcellular trafficking | Activity | Reference | ||||||
| TRPM6 |
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TRPM7 | Patch clamp | New channel creation | 24385424 | |||||||
| TRPM7 |
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TRPM6 | Patch clamp | New channel creation | 24385424 | |||||||
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click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
:
click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)