TRPM7, Magnesium, and Signaling.

Zhi-Guo Zou,Francisco J Rios,Rhian M Touyz,Augusto C Montezano

doi:10.3390/ijms20081877

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.

Highlights

The transient receptor potential melastatin 7 (TRPM7) and its close homologue TRPM6 share the unique feature of a cation channel fused to a C-terminal α-kinase domain [1,2,3]
TRPM7 and TRPM6 are unique proteins characterized by their channel and kinase domains, which differentially regulate cell signaling and function
TRPM6 and cellular Mg2+ homeostasis are regulated by EGF signaling through EGFR

Summary

Introduction

The transient receptor potential melastatin 7 (TRPM7) and its close homologue TRPM6 share the unique feature of a cation channel fused to a C-terminal α-kinase domain [1,2,3]. In 2009, Bindels and colleagues demonstrated that EGF activates EGFR signaling and promotes TRPM6 translocation from the cytosol to the membrane in kidney cells, through Src family tyrosine kinases [33]. These effects were abolished by the monoclonal antibody specific to EGFR (cetuximab) [33,34]. Similar effects were observed in mice treated with erlotinib [35] and in mammary epithelial cells treated with tyrphostin AG1478, inhibitors of EGFR tyrosine kinase [36] These studies were amongst the first to show a relationship between TRPM6, Mg2+ and growth factors and might explain the severe hypomagnesemia observed as a side effect in cancer patients treated with EGFR inhibitors [37]. Whether EGFR inhibitors influence TRPM7 in cancer patients is unclear

Characteristics and Regulation of TRPM7

Interactions between TRPM7 Kinase and TRPM7 Channel Domains

TRPM7and Kinase Signaling—Pathophysiological Implications

Findings

Conclusions and Perspectives