Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Transient Receptor Potential Cation Channel Subfamily M Member 7

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101913

Synonyms

Historical Background

Transient receptor potential (TRP) is a superfamily of channels that control the passage of cations across biological membranes (Yee et al. 2014). The TRP members share common features including intracellular amino and carboxyl termini, six transmembrane segments with the peptide between segments 5 and 6 forming the channel pore, and the TRP domain consisting of 23–25 amino acids highly conserved among all TRP members. TRP proteins are expressed in both electrically nonexcitable and excitable cells. TRP channels can be activated by changes in voltage or temperature, by ligand binding, or through covalent modification of amino acid residues. Channel activation typically leads to membrane depolarization and transmembrane flow of cations. These events form the basis of the functions of TRP channels as cellular sensors and transducers of physicochemical stimuli. These include light, heat, coolness, touch, force, pain, and taste. In response to those stimuli, the TRP channels can mediate a variety of physiological responses such as ionic homeostasis, muscular contraction, and vasomotor control. By modulating the associated signaling pathways, the TRP channels can control fundamental cellular processes including cell cycle progression, survival, differentiation, growth, and migration.

There are eight subfamilies in the vertebrate TRP family; they possess unique structural motifs and also share common architectural features. The TRP melastatin-like (TRPM) subfamily consists of eight members, and each exhibits distinct molecular, biophysical, and functional features (Yee et al. 2014). The amino terminus of each TRPM member contains four melastatin domains while the carboxyl termini vary in length and structure. All TRPM members contain a coiled-coil region (CCR) that is involved in channel multimerization. Enzymatic domains are present in TRPM2, TRPM6, and TRPM7. The TRPM channels show differential selectivity for cations. TRPM6 and TRPM7 primarily conduct Ca2+ and Mg2+; TRPM2 and TRPM8 are nonselective for cations. While TRPM4 and TRPM5 can influence Ca2+ entry through other channels by modulating the membrane potential, they are impermeable to divalent cations.

Among the eight TRPM channels, TRPM7 has been extensively studied and shown to be important in cellular and developmental biology, as well as in human diseases. The electrophysiological and biochemical properties as well as the structure-function relationship of TRPM7 have been analyzed. The biological functions of TRPM7 and its roles in embryonic development have been characterized in cultured cells and model organisms. The roles of TRPM7 in cancer and its potential as a tumor biomarker and therapeutic target for prevention, early detection, and personalized treatment of malignant diseases have emerged.

Structure of TRPM7 Channel-Kinase

TRPM7 is a ubiquitously expressed transmembrane channel selectively permeable for cations (Yee et al. 2014). It also possesses protein serine/threonine kinase activity. TRPM7 channel-kinase acts as a cellular sensor and transducer. Located on the long arm of human chromosome 15, the TRPM7 gene consists of 39 exons that span over 134.34 kb. Of the nine splice variants of this gene, four TRPM7 transcripts are protein encoding. The full-length human TRPM7 transcript is composed of 7263 nucleotides, and the TRPM7 protein is made up of 1865 amino acids (MW 210 kDa). The basic structural features of the TRPM7 protein are homologous and conserved among the TRPM members. TRPM7, and also TRPM6, contain an atypical α-type serine/threonine protein kinase domain in the carboxyl terminus. The channel pore-forming segment, the serine/threonine rich region, and the kinase domain together constitute the core components of TRPM7 for its functions (Fig. 1). The TRPM7 genes and the core functional domains protein are highly conserved in human, mouse, rat, and zebrafish (NCBI HomoloGene database).
Transient Receptor Potential Cation Channel Subfamily M Member 7, Fig. 1

Structural features of TRPM7 channel-kinase. The TRPM7 protein consists of six segments (S1–S6), each about 21 amino acids in length, across the plasma membrane. The channel pore (P) is formed between S5 and S6. The amino (N) and carboxyl (C) terminal portions are shown. In the pore-forming segment, the three negatively charged amino acids (E, E, and D) are important for regulating conductance of cations. Selected amino acid residues are indicated. aa indicates the amino acid position number in the human TRPM7 protein (This figure is adapted from Cells 2014, 3:751–777 with permission from the publisher)

The TRPM7 channel functions as a homotetramer. Four TRPM7 monomers assemble in a specific structural conformation presumably by protein interaction through the coiled-coil domain. Similarly, TRPM7/TRPM6 heterotetramers can be formed. Dimerization of TRPM7 through interaction between its α-type serine/threonine protein kinase domains has been demonstrated. The TRPM7 dimer can autophosphorylate and phosphorylate protein substrates. The two α-kinase domains of TRPM7 can assemble into a homodimer through interaction of the segment (residues 1551–1577) proximal to the kinase domain based on x-ray crystallography (Fig. 1). Consistent with this observation, the residues 1548–1576 of TRPM7 have been shown to be essential for monomeric interaction and kinase activity. Data from site-directed mutagenesis of TRPM7 indicate that the residues 1553–1562 are critical for kinase activity, and the residues 1563–1570 for dimerization.

Functions of TRPM7 Channel-Kinase

TRPM7 plays an important role in homeostasis of intracellular cations (Yee et al. 2014). The TRPM7 channel allows the flow of Mg2+ preferentially and to a lesser extent Ca2+. It permits other physiologically essential divalent cations including Zn2+, Mn2+, and Co2+. Environmentally toxic metals such as Ni2+, Cd2+, Ba2+, and Sr2+ are also permeable through the TRPM7 channel. In certain cell types, influx of Mg2+ through the TRPM7 channel can alter intracellular levels of Ca2+. Besides divalent cations, the TRPM7 channel is also permeable to H+. At physiological pH (7.4), the monovalent cationic currents are suppressed. At acidic pH, the binding affinity of TRPM7 for Mg2+ and Ca2+ decreases, and monovalent cations can flow through the TRPM7 channel. Indeed, TRPM7 exhibits inward proton conductance that can be inhibited by extracellular Ca2+ or Mg2+. These studies suggest that H+ can compete with Mg2+ and Ca2+ for binding sites in the TRPM7 channel pore.

Both TRPM7 and TRPM6 channels play a physiological role in epithelial reabsorption of Mg2+ and regulation of its total body homeostasis. While TRPM7 and TRPM6 are permeable to divalent cations, including Mg2+, heterotetramers of TRPM7 and TRPM6 can be formed, TRPM7 and TRPM6/7 channels exhibit distinct permeability, pH sensitivity, and conductance to divalent cations. Since the expression of TRPM6 is relatively restricted in the intestine and kidney, the relevant physiologically relevant TRPM7 channels are most likely in the form of homotetramers.

The TRPM7-mediated small inward currents at negative potentials are conducted by Mg2+ and Ca2+, whereas the large outward currents at positive potentials involve K+ and other monovalent ions. In the resting state, the channel activity of TRPM7 is inhibited by physiological levels of Mg2+ and Mg·ATP. The basal constitutive activity of TRPM7 channel is maintained by phosphatidylinositol 4,5-bisphosphate (PIP2) in the vicinity of the channel. The TRPM7 channel can be activated by depletion of intracellular free Mg2+ ([free Mg2+]ic) or Mg·ATP, by intracellular alkalinization, and also by cyclic adenosine monophosphate (cAMP). Suppression of the TRPM7 channel activity can be attained by high [Mg·ATP]ic, high [free Mg2+]ic (IC50 of 0.6 mM), cytosolic acidity (IC50 of pH 6.3), spermine, or by depletion of PIP2 (by activation of phospholipase C). The inhibitory effect of Mg2+ic on TRPM7 channel activity can be enhanced by halides (Cl, Br, I), and this involves the ATP-binding site in its kinase domain. Taken together, these studies support the role of TRPM7 channel as a cellular sensor of various physicochemical changes in the extracellular medium and in the cytosol.

As a member of the α-kinase family, TRPM7 can autophosphorylate its serine (predominantly) and threonine residues. The majority of the autophosphorylation sites were mapped to the Ser/Thr-rich region. Autophosphorylation of TRPM7 facilitates phosphorylation of its substrates without affecting its catalytic activity. Phosphorylation of annexin 1 and the heavy chain of myosin IIA by TRPM7 suggests its role in vesicle fusion, actomyosin contractility, and cell adhesion. Besides, TRPM7 kinase phosphorylates phospholipase γ2 (PLCγ2) at the serine/threonine sites in its C2-domain. This suggests that the sensitivity of TRPM7 channel to Mg2+ may be mediated through phosphorylation of serine/threonine in PLCγ2. Moreover, TRPM7 regulates Mg2+-dependent phosphorylation of the translational factor eEF2 through eEF2-kinase. While the TRPM7 kinase is positively regulated by Mg·ATP, the kinase activity is impaired by either cytosolic acidity (pH 4.0) or alkalinity (pH 8.4 or 9.0). These data provide support for the important roles of the kinase in the TRPM7-mediated functions.

TRPM7 Channel and Kinase Are functionally Coupled

The kinase activity of TRPM7 and its channel function are inter-related (Table 1). Kinase-inactivating mutations of residues in the ATP- or Zn2+-binding sites within the kinase domain reduced TRPM7-mediated currents. Mutations of two autophosphorylation sites or a key catalytic site caused inactivation of the kinase without affecting TRPM7-mediated currents or Ca2+ influx. However, the channel sensitivity of TRPM7 can be modulated by its kinase activity. TRPM7 mutants with deficient phosphotransferase activity displayed decreased [Mg2+]ic- or [Mg·ATP]ic-induced channel inhibition, but full channel activation in response to low [free Mg2+]ic. Furthermore, cAMP-mediated potentiation of channel activity and GTPγS-mediated inhibition of channel activity were abolished in phosphotransferase-deficient TRPM7 expressing cells. Moreover, the kinase domain of TRPM7 plays a regulatory role in its channel activity. Deletion of TRPM7 kinase domain (TRPM7ΔKD) enhanced [Mg2+]ic- or [Mg·ATP]ic- mediated suppression of channel activity, and also abrogated cAMP-mediated activation of the channel. In one study, most of the TRPM7 channel activity was diminished by deletion of its kinase domain. Results of these studies indicate that the channel function of TRPM7 and its kinase activity are functionally linked.
Transient Receptor Potential Cation Channel Subfamily M Member 7, Table 1

Molecular determinants of TRPM7 channel-kinase activity. The amino acids and the associated functions as determined by site-directed mutagenesis of TRPM7. aa amino acids, h human, m mouse (This table is adapted from Cells 2014, 3:751–777 with permission from the publisher)

Mutations of amino acids

Effect on TRPM7 function

Channel pore forming segment (Human, aa. 1036–1056)

m E1047Q (Glu → Gln) or h E1047A (Glu → Ala)

Loss of channel permeability to Mg2+ and Ca2+

m E1052Q (Glu → Gln)

Decreased Mg2+ and Ca2+ binding, and reduced Mg2+ and Ca2+ currents

h E1052A (Glu → Ala)

Decreased Mg2+ and Ca2+ binding, and reduced Mg2+ and Ca2+ currents. Partial reduction of proton conductivity

h D1054A (Asp → Ala)

Loss of proton conductivity

h D1059A (Asp → Ala)

Partial reduction of proton conductivity

Serine/threonine rich region (Human, aa. 1380–1596)

h T1482I (Thr → Ile) (a natural variant) (autophosphorylation site)

Increased sensitivity of channel to Mg2+-mediated suppression, and decreased current even at reduced (Mg2+)

m D1510 (Asp)

Caspase-mediated cleavage at Asp-1510 resulted in up-regulated channel activity

m S1511A (Ser → Ala) (autophosphorylation site)

No change in Ca2+ influx or sensitivity to Mg2+-mediated inhibition

m S1567A (Ser → Ala) (autophosphorylation site)

No change in Ca2+ influx or sensitivity to Mg2+-mediated inhibition

m Y1553F (Tyr → Phe)

~75% of wild-type kinase activity

m Y1553L (Tyr → Leu)

~50% of wild-type kinase activity

m Y1553A (Tyr → Ala)

~35% of wild-type kinase activity

m R1558A (Arg → Ala)

~15% of wild-type kinase activity

Kinase domain (Human, aa. 1597–1824)

m R1622L (Arg → Leu) (binding of PO43− of ATP)

<1% of wild-type kinase activity

h K1648R (Lys → Arg) or (phosphotransfer activity)

Diminished kinase activity

No change in channel activation in response to decreased free Mg2+ or Mg·ATP

Attenuated suppression of channel activity in response to free Mg2+ or Mg·ATP

m K1646R (Lys → Arg) (phosphotransfer activity)

<1% of wild-type kinase activity

m K1727A (Lys → Ala)

<1% of wild-type kinase activity

m N1731V (Asn → Val) (binding of PO43− of ATP)

<1% of wild-type kinase activity

m E1760A (Glu → Ala)

~15% of wild-type kinase activity

m D1765N (Asp → Asn) or m D1765A (Asp → Ala)

<1% of wild-type kinase activity

m Q1767N (Gln → Asn) or m Q1767A (Gln → Ala) (metal binding)

<1% of wild-type kinase activity

m T1774S (Thr → Ser) m T1774A (Thr → Ala) (binding of PO43− of ATP)

<1% of wild-type kinase activity

~6% of wild-type kinase activity

m D1775A (Asp → Ala) (metal binding)

<1% of wild-type kinase activity

m N1795A (Asn → Ala) (binding of peptide substrate)

~2% of wild-type kinase activity

h G1799D (Gly → Asp) (phosphotransfer activity)

Diminished kinase activity

No change in channel activation in response to decreased free Mg2+ or Mg·ATP

Attenuated suppression of channel activity in response to free Mg2+ or Mg·ATP

Studies of endogenously expressed TRPM7 have generated further insights into the role of its kinase and the relationship with its channel function. In T-lymphocytes, Fas-receptor-induced apoptosis involves caspase-dependent cleavage of TRPM7 at the Asp-1510 residue. This results in upregulation of the TRPM7 channel activity and dissociation of the kinase domain from the channel pore. In tissues and cell lines, TRPM7’s kinase is proteolytically removed from its channel domain. The released kinase then binds to the Zn2+-binding domain of transcription factors, leading to modification of chromatin through histone phosphorylation. These data suggest that TRPM7’s channel controls cellular influx of Zn2+ for the functions of chromatin-modifying kinase, and further support a functional link between the channel and kinase of TRPM7.

A reciprocal relationship between the channel function of TRPM7 and its kinase domain/activity has been demonstrated. Cations, including Mg2+, Ca2+, H+, and Zn2+, conducted by TRPM7’s channel regulate its kinase activity and function. TRPM7’s kinase in turn modulates its channel function in response to [Mg2+]ic, [Mg⋅ATP]ic and receptor-mediated signaling that involves cAMP and GTPγS. The molecular basis for the inter-relationship between the TRPM7 channel and kinase activities, as well as the channel’s permeability to Mg2+, Ca2+, and H+, pH sensitivity is summarized in Table 1. It is noteworthy that the biological significance of the channel and kinase activities of TRPM7 likely depends on the cell type and the molecular context. Nonetheless, knowledge of the molecular determinants is important for understanding the various functions of TRPM7, and expected to provide insights into the mechanisms underlying its roles in normal physiology and disease states.

Normal Cellular Functions of TRPM7 Channel-Kinase

The TRPM7 channel-kinase plays important roles in cellular survival, proliferation, senescence, differentiation, growth, autophagy, and migration (Table 2). In most cell types, silenced expression of TRPM7 impairs cell cycle progression and survival, suggesting an essential requirement of TRPM7 for these cellular events. On the other hand, TRPM7 is responsible for cell death of anoxic neurons and umbilical vein vascular endothelia, implying an antisurvival role of TRPM7 in neurons and vascular endothelia. The opposing effects of silencing TRPM7 on growth and migration of human microvascular endothelial cells and human umbilical vein endothelial cells may be attributed to different status of phospho-ERK. These data indicate that the functional roles of TRPM7 vary among cell types and depend on the molecular context.
Transient Receptor Potential Cation Channel Subfamily M Member 7, Table 2

Normal functional roles of TRPM7 channel-kinase (This table is adapted from Cells 2014, 3:751–777 with permission from the publisher)

Cell type

Functional roles of TRPM7 channel-kinase

Lymphocytes

Required for Mg2+-dependent viability and proliferation of chicken B lymphocytes (DT-40)

Required for proliferation involving phosphoinositide 3-kinase

Required for differentiation

Required for survival of T lymphocytes by preventing Fas-induced apoptosis

Neurons

Oxidative stress activates TRPM7, which mediates anoxic death in human neurons; suppression of TRPM7 prevents anoxic neuronal death

Facilitates fusion of cholinergic vesicle with plasma membrane and neurotransmitter release in cholinergic synaptic vesicles

Interstitial cells of Cajal

Required for pacemaker activity of mouse duodenum

Expressed in the interstitial cells of Cajal of human colon and small intestine and involved in the generation of the slow waves

Melanoblasts

Required for survival of melanophores in zebrafish larvae

Vascular smooth muscle cells

Functional TRPM7 channels translocate to plasma membrane in response to fluid flow

Angiotensin II promotes proliferation of VSMCs in ascending aorta by increasing TRPM7 protein via Ca2+-influx-mediated activation of the Pyk2-ERK1/2-Elk-1 pathway

Osteoblasts

Required for platelet-derived growth factor-induced proliferation and migration of human osteoblast MG-63 cells

Cervical epithelia

Required for volume regulation as TRPM7-like currents activated by osmotic swelling-induced mechanical stretch of human cervical cancer HeLa cells

Mast cells

Required for survival of human lung mast cells and human mast cell lines (LAD2, HMC-1)

Fibroblasts

Membrane tension activates TRPM7 channels and Ca2+ flickers, directing migration in human embryonic lung fibroblasts

Transforming growth factor-β increased expression of TRPM7 in human atrial fibroblasts associated with myofibroblast differentiation and fibrogenesis in atrial fibrillation

Vascular endothelia

Silencing TRPM7 promotes growth/proliferation and nitric oxide production via ERK in human umbilical vein vascular endothelial cells (HUVECs)

Silencing TRPM7 inhibits growth and migration of human microvascular endothelial cells (HMEC) but stimulates growth of HUVECs, partly because of impaired phosphorylation of ERK in HMEC

Inhibition of TRPM7 leads to increased cell growth and migration in HUVECs

TRPM7 contributes to hyperglycemia-induced injury of HUVECs

Bone marrow-derived mesenchymal stem cells

Required for survival of mouse bone marrow-derived mesenchymal stem cells; expression increased during osteogenesis suggesting its involvement in differentiation

Embryonic stem cells

Kinase domain, but not kinase activity, is required for proliferation of mouse embryonic stem cells

Pancreatic epithelia

Required for proliferation, cell cycle progression, and growth involving Mg2+ and Soc3a in exocrine pancreatic epithelia of zebrafish larvae

Hepatic stellate cells

- Required for survival by preventing TRAIL-induce apoptosis

- Regulates platelet-derived growth factor-BB-induced proliferation via PI3K and ERK in a rat hepatic stellate cell line (HSC-T6)

- Required for activation and proliferation of HSCs by preventing endoplasmic reticulum stress-mediated apoptosis

Atrial myocytes

- TRPM7-like current was recorded in human atrial myocytes, and expression of TRPM7 is upregulated in atria with atrial fibrillation or membrane rupture

Kidney cells

- TRPM7 contributes to the elevated level of reactive oxygen species that leads to cell rounding mediated by the p38 MAPK/JNK-dependent activation of the Ca2+-dependent protease calpain in the immortalized human embryonic kidney cells (HEK 293), and during ischemia reperfusion in the mouse transplanted kidney

The normal physiological functions of TRPM7 are reflective of its fundamental roles in cellular processes including regulation of vascular tone, intestinal peristalsis, synaptic neurotransmission, and bone growth (Table 2). These indicate the capability of TRPM7 to sense and transduce signals of mechanical stress from blood flow, food digestion and absorption, cervical stretch, skeletal support, and wound healing. Moreover, TRPM7 is implicated in ischemia associated with reperfusion of transplanted kidney, cardiac atria with fibrillation or membrane rupture, and hyperglycemia-induced injury in vascular endothelia. Results of these studies implicate a TRPM7-mediated protective mechanism in response to metabolic and oxidative stress under the pathological conditions of those organs.

The TRPM7-mediated functions involve interactions and modulations of the signaling pathways induced by stress, mitogens, and cytokines. As illustrated in Fig. 2, a working model is proposed for the signaling mechanism of TRPM7 channel-kinase. The TRPM7 channel-kinase acts as a cellular sensor of the physicochemical stimuli such as mechanical stretch, changes in cell volume or osmolar gradient, oxidative stress, and alterations in cytosolic or extracellular pH. By acting as a signal transducer, TRPM7 controls passage of ions and modulates the signaling pathways that mediate the cellular responses of mitogens and cytokines. The role of TRPM7 channel-kinase as a cellular sensor and transducer of physicochemical stimuli is not only important in normal physiology, but also various aspects of embryonic development.
Transient Receptor Potential Cation Channel Subfamily M Member 7, Fig. 2

TRPM7-mediated signaling mechanisms. The TRPM7 channel and kinase are constitutively active in resting cells. By responding to cytosolic or extracellular stimuli or stress, the TRPM7 channel regulate Ca2+ and Mg2+ fluxes into or out of the cells. The TRPM7 kinase can autophosphorylate and phosphorylate various cytosolic substrates. The resulting perturbation of ionic homeostasis and trigger of phosphorylating events lead to activation or inhibition of the epidermal growth factor- or other cytokines-induced signaling components. As a consequence, the target genes are being transcribed and translated to mediate cellular proliferation, survival, differentiation, growth, adhesion, rounding, and migration (This table is adapted from Cells 2014, 3:751–777 with permission from the publisher)

TRPM7 Channel-Kinase in Embryonic Development

Studies using model animals have elucidated the pleiotropic roles of TRPM7 in early development and organogenesis (Table 3). Homozygous deletion of Trpm7 is embryonic lethal in mouse, suggesting an essential role of Trpm7 in viability of embryos. Selective deletion of the TRPM7 channel in xenopus indicates that the TRPM7 channel activity is crucial for gastrulation. Zebrafish embryos with loss-of-function mutations in trpm7 are viable, and the mutant larvae are capable of developing various organs. The organogenic roles of Trpm7 have also been implicated by studies using genetically engineered mice with tissue-specific mutation of Trpm7. Data from the zebrafish and mouse models support a functional requirement of the TRPM7 channel-kinase for normal development of skin pigment, nervous system, kidney, skeleton, thymus, and exocrine pancreas (Table 3). Depending on the organ systems involved, TRPM7-mediated conductance of Mg2+ and/or Ca2+ plays a crucial role in various cellular processes including survival, cell cycle progression, proliferation, growth, differentiation, and morphogenesis. For instance, zebrafish larvae with loss-of-function mutations in trpm7 develop exocrine pancreas with hypomorphic ducts and acini (Yee et al. 2011). Anti-socs3a oligos partially rescued the phenotype of exocrine pancreas, suggesting Socs3a plays a negative regulatory role in Trpm7-regulated exocrine pancreatic development. Consistent with the negative requirement of Socs3a in zebrafish, STAT3 positively controls TRPM7-regulated differentiation and maintenance of thymic epithelia in mouse. These findings suggest conserved signaling mechanisms that mediate the developmental roles of TRPM7. Future studies of TRPM7 are expected to shed new light into its biological mechanisms in development and in diseases states particularly cancer.
Transient Receptor Potential Cation Channel Subfamily M Member 7, Table 3

Developmental roles of TRPM7 channel-kinase (This table is adapted from Cells 2014, 3:751–777 with permission from the publisher)

Developmental processes

Mutant phenotypes

Functional roles

Embryogenesis

- Early embryonic lethality between E 6.5 and E7.5 in mouse

- Required for intestinal absorption of Mg2+ and whole body magnesium homeostasis

Gastrulation

- Defects in cell polarization and alignment during convergent extension in Xenopus

- TRPM7 channel but not the kinase domain required for regulating polarized cell movements during gastrulation involving Mg2+ via noncanonical Wnt signaling and modulation of the small GTPase Rac levels

Melanogenesis

- Skin hypopigmentation in zebrafish larvae

- Required for survival of melanophores in zebrafish larvae

- Loss-of-function mutation in Trpm7 leads to cell death of melanophores that is dependent on melanin synthesis

Skeletogenesis

- Skeletal deformities in zebrafish with accelerated endochondral ossification and delayed intramembranous ossification

- Dwarf zebrafish adults

- Not reported

Thymopoiesis

- Selective deletion of Trpm7 in

T-cell lineage accelerates thymic involution in mouse

- Required for differentiation and

maintenance of thymic epithelia

- Required for STAT3 activity in thymic medullary cells

Nervous system

- Defects in touch-response in

zebrafish larvae

- Paralysis of hind legs of mouse

with deletion of Trpm7 in committed neural crest progenitors; loss of large-diameter sensory

neurons in lumbar dorsal root ganglion of mouse embryos depleted of TRPM7

- Possibly required for synaptic release of neurotransmitters between sensory neurons and interneurons in zebrafish larvae

- Required for development of neural crest progenitors into dorsal root ganglion sensory neurons in mouse

- Required for differentiation or function of dopaminergic neurons in zebrafish larvae

Nephrogenesis

- Nephrolithiasis in zebrafish

larvae

- Defect formation of kidney with

relatively few glomeruli and large

renal cysts in mouse

- Required for homeostasis of whole body

Mg2+ and Ca2+ in zebrafish involving stanniocalcin 1 and fibroblast growth factor

23

Exocrine pancreatic organogenesis

- Relatively small pancreas with immature acini and hypomorphic ducts in zebrafish larvae

- Required for pancreatic epithelial proliferation and growth, which are sensitive to Mg2+ in extracellular medium and involving Socs3a

Expression and Roles of TRPM7 in Diseases

Accumulating evidence has demonstrated that TRPM7 is involved in a variety of diseases in human and experimental animal models. Consistent with its function in Mg2+ and Ca2+ homeostasis, TRPM7 plays an etiologic role in hypomagnesemia with secondary hypocalcemia (Chubanov et al. 2004). TRPM7 is important in a number of neurological diseases. These include anoxic neuronal death (Aarts et al. 2003), guamanian neurodegenerative disorders (Hermosura et al. 2005), cerebral ischemia (Romero et al. 2009; Sun et al. 2013), Zn2+-induced neurotoxicity (Inoue et al. 2010), hydrogen peroxide-induced neurodegeneration (Coombes et al. 2011), and 6-hydroxydopamine-induced Parkinson’s disease (Yang et al. 2016). Besides, TRPM7 has been implicated in cardiovascular diseases such as atrial fibrillation (Du et al. 2010), ventricular tachycardia (Parajuli et al. 2015), vascular hypertension (Yogi et al. 2011), angiotensin II-induced hypertension (Antunes et al. 2016), and phosphate-induced calcification in aortic vascular muscle cells (Louvet et al. 2013). TRPM7 is also involved in oxidative stress-induced hepatic fibrosis (Zhu et al. 2014), treatment effect of calcitriol on vascular calcification in chronic kidney disease (Zelt et al. 2015), and airway remodeling induced by cigarette smoke exposure (Lin et al. 2016). Numerous studies have examined the expression, functional roles, and clinical significance of TRPM7 in cancer and they are summarized as follows.

TRPM7 channels play contributory roles in a variety of human malignant diseases (Table 4). In pancreatic adenocarcinoma, breast carcinoma, and head/neck cancer, and glioblastoma, TRPM7 is aberrantly over-expressed in cell lines and /or tissues. Studies using cancer cell lines indicate that TRPM7 regulate a variety of cellular processes including survival, cell cycle progression, proliferation, migration, invasion, and epithelial-mesenchymal transition (Table 4). Consistent with these findings in cancer cells, results of the study using mouse xenograft of human breast cancer showed that TRPM7 is required for tumor growth and metastasis. These studies support the hypothesis that TRPM7 channel-kinase acts as a sensor and transducer of physicochemical stimuli in the cells and their microenvironment and contribute to the multistep processes of carcinogenesis.
Transient Receptor Potential Cation Channel Subfamily M Member 7, Table 4

Expression and roles of TRPM7 channels in various human malignancies (This table is adapted and modified from Cells 2014, 3:751–777 with permission from the publisher)

Cancer

Expression

Functional roles of TRPM7

Pancreatic adenocarcinoma

- Increased in human pancreatic adenocarcinoma tissues and cell lines

- Increased in chronic pancreatitis, pancreatic intraepithelial neoplasms

- Required for cellular proliferation and cell cycle progression involving Mg2+

- Required for preventing replicative senescence

- Required for cell migration involving Mg2+

- Required for cell invasion

Breast carcinoma

- Over-expression in human breast carcinoma tissues and cell lines

- Increased expression in infiltrating ductal carcinoma with microcalcifications

- Somatic mutation T720S (Thr → Ser) in a breast infiltrating ductal carcinoma

- Required for cancer cell proliferation in vitro

- Required for cancer cell migration in vitro and tumor metastasis in a mouse xenograft model

- Waixenicin A, TRPM7 blocker, inhibits growth and survival of breast cancer cells MCF-7

- TRPM7 involved in estrogen receptor-negative metastatic breast cancer cells migration through kinase domain

- Involved in ginsenoside Rd-induced apoptosis in cells

- Involved in epithelial mesenchymal transition

- TRPM7 mediates migration and invasion of breast cancer cells (MDA-MB-435) involving phosphorylation of Src and MAPK

Gastric carcinoma

- Expressed in human

gastric adenocarcinoma cell lines (AGS, MKN-1, MKN-45, SNU-1, SNU-484)

- Somatic mutation M830 V (Met → Val) in gastric adenocarcinoma

- Required for cell survival involving Mg2+

- Waixenicin A, TRPM7 blocker, inhibits growth and survival of gastric cancer cells AGS

- Involved in ginsenoside Rd.-induced apoptosis AGS cells

Head and neck

Carcinoma

- Expressed in FaDu cells and SCC-25 cells

- High expression in 5–8F cells, low expression in 6–10B cells

- Required for cell growth and proliferation

- Required for migration of nasopharyngeal carcinoma cells (5–8F and 6–10B)

- Proliferation of FaDu hypopharyngeal squamous cells (FaDu) inhibited by midazolam that targets TRPM7

Retinoblastoma

- Existence in 5–8F cells

- Required for cell proliferation

- Required for 5-8F cell migration

Melanoma

- Expressed in cell lines

- Not reported

Lung carcinoma

- Expressed in A549 cells

- Required for migration of A549 cells

Erythroleukemia

- TRPM7-like currents in cell lines

- Not reported

Colon cancer

-TRPM7 (Thr1482Ile) polymorphism

- TRPM7 (Thr1482Ile) polymorphism associated with elevated risk of both adenomatous and hyperplastic polyps

- Individuals with TRPM7 (Thr1482Ile) polymorphism with a high Ca:Mg ratio intake in diet at a relatively high risk of developing adenoma and hyperplastic polyps

Leukemia

- Not reported

- Waixenicin inhibits and T cell leukemia (Jurkat T

lymphocytes) and rat basophilic leukemia cells

(RBL1) through blocking TRPM7 channel activity

Neuroblastoma

- Not reported

- In mouse neuroblastoma cells (N1E-115), TRPM7 promotes formation of Ca2+ sparking and invadosome by affecting actomyosin contractility independent from Ca2+ influx

Ovarian carcinoma

- Somatic mutation S406C (Ser → Cys) in ovarian serous carcinoma

- Not reported

Prostate cancer

- Expressed in human prostate cancer cell line DU145

- Increased Ca2+ to Mg2+ ratio in prostate cancer cells enhances TRPM7-mediated currents and promotes cellular entry of Ca2+, leading to increase in cell proliferation

Glioblastoma

- Overexpressed in human glioblastoma cell line U87

Chemical inhibition of TRPM7 using carvacrol, xylokeletal, or midazolam induces cell cycle arrest and suppresses cell proliferation, migration, and invasion

Besides, the aberrant expression of TRPM7 in cancer suggests the potential of TRPM7 being developed as predictive and prognostic biomarkers in malignant diseases. Epidemiological studies provide evidence that the TRPM7 variant T1482I (previously identified in patients with neurodegenerative diseases) is associated with dietary intake of Ca2+/Mg2+ and colonic adenoma/polyps. This may help develop strategy for early detection and screening of colon cancer as well as prevention of colon cancer through dietary interventions. On the other hand, a positive correlation was demonstrated between the aberrant overexpression of TRPM7 in pancreatic adenocarcinoma and the tumor size and stage (Yee et al. 2015). These findings suggest a potential role of TRPM7 as a biomarker for prognosis in patients with pancreatic cancer.

Moreover, the proliferative and proinvasion roles of TRPM7 in cancer cells suggest the opportunity of targeting TRPM7 for novel strategies of developing antitumor therapeutics. Chemical inhibitors of TRPM7 channel activity have been demonstrated to produce antiproliferative effects in a variety of cancer cells such as gastric adenocarcinoma, breast adenocarcinoma, and glioblastoma. The discovery that RNA interference-mediated silencing of TRPM7 induces replicative senescence in pancreatic adenocarcinoma cell lines supports a novel therapeutic approach to combine with the chemotherapeutic drug gemcitabine for enhancing cytotoxicity (Yee et al. 2012). Furthermore, a potential role of TRPM7 in tumor-specific delivery of anticancer agents in malignant diseases can be exploited.

Summary

The TRPM7 channel-kinase is a ubiquitously expressed cellular sensor and transducer of physicochemical stimuli that plays important roles in normal bodily functions and disease states. Analysis of the structure of TRPM7 and the molecular determinants of its electrophysiological functions indicate that the channel and kinase are functionally coupled. TRPM7 plays crucial roles in diverse cellular events including survival, growth, differentiation, autophagy, proliferation, and migration. The TRPM7-mediated functions regulate diverse physiological processes, as well as early embryonic development and organogenesis. The signaling pathways that mediate the various functions of TRPM7 may depend on the cell type and molecular context. The pathophysiological roles of TRPM7 have been demonstrated in a variety of diseases that affect major vital organs. The aberrant expression of TRPM7 in malignant neoplasms and its requirement for the malignant phenotypes implicate TRPM7 in the multisteps of tumor formation and progression. The finding of genetic mutations and alleles of the TRPM7 gene suggest the potential of exploiting it as a clinical biomarker for prevention and early detection of cancer. Identification and testing of chemical modulators of TRPM7 expression and channel activity offer new opportunity of developing them as therapeutic agents toward the goal of precision oncology.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Medicine, Division of Hematology-OncologyPennsylvania State University, Milton S. Hershey Medical Center, PennState Cancer InstituteHersheyUSA