Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Apr 16;20(8):1877.
doi: 10.3390/ijms20081877.

TRPM7, Magnesium, and Signaling

Zhi-Guo Zou  1 , Francisco J Rios  2 , Augusto C Montezano  3 , Rhian M Touyz  4
Affiliations
Review

TRPM7, Magnesium, and Signaling

Zhi-Guo Zou et al. Int J Mol Sci. .

Abstract

The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed chanzyme that possesses an ion channel permeable to the divalent cations Mg2+, Ca2+, and Zn2+, and an α-kinase that phosphorylates downstream substrates. TRPM7 and its homologue TRPM6 have been implicated in a variety of cellular functions and is critically associated with intracellular signaling, including receptor tyrosine kinase (RTK)-mediated pathways. Emerging evidence indicates that growth factors, such as EGF and VEGF, signal through their RTKs, which regulate activity of TRPM6 and TRPM7. TRPM6 is primarily an epithelial-associated channel, while TRPM7 is more ubiquitous. In this review we focus on TRPM7 and its association with growth factors, RTKs, and downstream kinase signaling. We also highlight how interplay between TRPM7, Mg2+ and signaling kinases influences cell function in physiological and pathological conditions, such as cancer and preeclampsia.

Keywords: EGFR; TRPM7; VEGFR; magnesium transporters; receptor tyrosine kinases.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic structure of the TRPM7 channel and kinase. The general structure of the TRPM7 has four Melastatin Homologous Regions (MHR) in the N-terminal domain, and six transmembrane segments (aa 756–1095). The pore (aa 1039–1056) is located between the S5 and S6. The C terminal domain contains the transient receptor potential (TRP) region (aa 1109–1128), common to TRP family members, followed by the coiled coil (CC) domain connecting loop (aa 1198–1250); Serine- and threonine-rich domains (aa 1380–1596), and the α-kinase domain (aa 1597–1821).
Figure 2
Figure 2
Schematic overview of TRPM7 mutations. Mutations that have been identified are highlighted. Numbers indicate the single amino acids or regions that affect TRPM7 channel or kinase activity [17,19,46,48,49,54,55,56,57,58,59].
Figure 3
Figure 3
Transphosphorylation of TRPM7 by TRPM6. TRPM6 is able to induce phosphorylation of TRPM7 in the indicated residues. Red stars indicate the location of the residues. Residues in blue are also residues of autophosphorylation.
Figure 4
Figure 4
Importance of Mg2+ for the kinase catalytic activity. Two Mg2+ molecules are required for enzymatic activity and phosphoryl transfer: one bound to ATP (Mg-ATP) situated between the small (N-lobe) and large lobe (C-Lobe) of the kinase domain, and another Mg2+ situated in the catalytic loop. (1) Mg-ATP is the first to bind to the enzyme followed by Mg2+; (2) the kinase binds to the protein substrate and catalyzes the transfer the phosphoryl group; (3) phosphorylated protein and Mg2+ are released; and (4) Mg-ADP is released and the catalytic cycle is finalized.
Figure 5
Figure 5
Schematic representation of main signaling pathways activated by growth factor signaling through receptor tyrosine kinases (RTK) and the importance of Mg2+. Ligand-induced dimerization triggers transphosphorylation of tyrosine residues located in the receptor chain, resulting in activation of RTKs. Intracellular signaling cascades activated by RTKs include the MAPK pathway, the PI3K/AKT/mTOR pathway, the JAK/STAT pathway, the PLCγ/PKC pathway and the Src pathway. The functional response of these signals plays an essential role in the regulation of many physiological processes. Dotted arrows indicate activation through the cell membrane; Solid arrows indicate activation of target protein; T indicates inhibition.
Figure 6
Figure 6
Cross-talk between Receptor Tyrosine Kinases (RTK) downstream signaling and TRPM7. TRPM7 has the dual properties of acting as an ion channel mainly permeable to Zn2+, Mg2+ and Ca2+, and as a cytoplasmic kinase, which phosphorylates annexin-1, myosin IIA heavy chain, eEF2, SMAD2, and PLCγ2. Through either its channel or kinase, TRPM7 participates in RTK downstream signaling pathways. On the other hand, ligand induced activation of RTKs, such as EGFR, regulates the activity of TRPM7 or TRPM6. Signaling by bradykinin, Ang II, and IL-18 also influence TRPM7 activity. Dotted arrows indicate activation through the cell membrane; Solid arrows indicate activation of target protein; T indicate inhibition.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Clapham D.E. TRP channels as cellular sensors. Nature. 2003;426:517–524. doi: 10.1038/nature02196. - DOI - PubMed
    1. Levitan I.B., Cibulsky S.M. Biochemistry. TRP ion channels--two proteins in one. Science. 2001;293:1270–1271. doi: 10.1126/science.1062504. - DOI - PubMed
    1. Duan J., Li Z., Li J., Hulse R.E., Santa-Cruz A., Valinsky W.C., Abiria S.A., Krapivinsky G., Zhang J., Clapham D.E. Structure of the mammalian TRPM7, a magnesium channel required during embryonic development. Proc. Natl. Acad. Sci. USA. 2018;115:E8201–E8210. doi: 10.1073/pnas.1810719115. - DOI - PMC - PubMed
    1. Park H.S., Hong C., Kim B.J., So I. The Pathophysiologic Roles of TRPM7 Channel. Korean J. Physiol. Pharmacol. 2014;18:15–23. doi: 10.4196/kjpp.2014.18.1.15. - DOI - PMC - PubMed
    1. Nadolni W., Zierler S. The Channel-Kinase TRPM7 as Novel Regulator of Immune System Homeostasis. Cells. 2018;7:109. doi: 10.3390/cells7080109. - DOI - PMC - PubMed

Substances