The channel kinase,
            <i>TRPM7</i>
            , is required for early embryonic development

sient receptor potential melastatin 7 (TRPM7) is a nonselective cation channel with an ␣-kinase domain in its COOH terminal, known to play a role in diverse physiological and pathological processes such as Mg 2ϩ homeostasis, cell proliferation, and hypoxic neuronal injury. Increasing evidence suggests that TRPM7 contributes to the physiology/pathology of vascular systems. For example, we recently demonstrated that silencing TRPM7 promotes growth and proliferation and protects against hyperglycemia-induced injury in human umbilical vein endothelial cells (HUVECs). Here we investigated the potential effects of TRPM7 on morphology, adhesion, migration, and tube formation of vascular endothelial cells and the potential underlying mechanism. We showed that inhibition of TRPM7 function in HUVECs by silencing TRPM7 decreases the density of TRPM7-like current and cell surface area and inhibits cell adhesion to Matrigel. Silencing TRPM7 also promotes cell migration, wound healing, and tube formation. Further studies showed that the extracellular signalregulated kinase (ERK) pathway is involved in the change of cell morphology and the increase in HUVEC migration induced by TRPM7 silencing. We also demonstrated that silencing TRPM7 enhances the phosphorylation of myosin light chain (MLC) in HUVECs, which might be involved in the enhancement of cell contractility and motility. Collectively, our data suggest that the TRPM7 channel negatively regulates the function of vascular endothelial cells. Further studies on the underlying mechanism may facilitate the development of the TRPM7 channel as a target for the therapeutic intervention of vascular diseases.

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“…2ϩ levels between control and TRPM7 siRNAs was not detected, consistent with previous studies performed in knockout mice (34,35,61) (Fig. 1E).…”

Section: Mgsupporting

confidence: 92%

TRPM7 regulates vascular endothelial cell adhesion and tube formation

Zeng

Inoue

Sun

et al. 2015

American Journal of Physiology-Cell Physiology

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“…15,16 However, the functional role of TRPM7-mediated Ca 2+ signaling in the phenotypic switching of VSMCs has not been explored.…”

mentioning

confidence: 99%

“…14 Moreover, TRPM7 is essential for embryonic development, as evidenced by genetic ablation leading to embryonic lethality. 15,16 However, the functional role of TRPM7-mediated Ca 2+ signaling in the phenotypic switching of VSMCs has not been explored.…”

mentioning

confidence: 99%

Upregulation of TRPM7 Channels by Angiotensin II Triggers Phenotypic Switching of Vascular Smooth Muscle Cells of Ascending Aorta

Zhang

Wang

Fan

et al. 2012

Circulation Research

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Rationale: Angiotensin II (Ang II) has pleiotropic effects on vascular smooth muscle cells (VSMCs). It has been demonstrated to promote the proliferative phenotype of VSMCs in mouse ascending aorta, but the underlying mechanisms remain incompletely understood.Objective: The present study was designed to explore whether the Ca 2+ -permeable transient receptor potential melastatin 7 (TRPM7) channel is involved in Ang II-induced phenotype switching of ascending aortic VSMCs and to dissect the molecular mechanisms by which TRPM7 modulates VSMC phenotype. Methods and Results:As revealed by current recording, Ang II infusion increased TRPM7 whole-cell currents in ascending aortic VSMCs. The increase in TRPM7 currents was found to result from enhanced expression of TRPM7 protein rather than elevated single-channel activity (open probability and slope conductance) and/ or reduced Mg 2+-mediated channel block. Mechanistically, Ang II elevated TRPM7 expression via Ang II type 1 receptor-mediated ERK1/2 signaling. As indicated by the expression levels of VSMC differentiation marker genes, phenotypic switching of ascending aorta occurred during Ang II infusion. Meanwhile, ERK1/2-Elk-1 signaling pathway known to suppress VSMC differentiation was activated in Ang II-infused ascending aorta. Knockdown of TRPM7 with small interfering RNA established a causative role of TRPM7 in Ang II-induced phenotypic change and promotion of cell proliferation. Moreover, TRPM7 was shown to be required for Pyk2-ERK1/2-Elk-1 pathway activation by Ang II, which potentiated TRPM7 channel function and thus activated the Ca formation in the animal model of vascular injury. 5 All the evidence converges to highlight the importance of finely tuned Ca 2+ signaling in VSMC homeostasis. Transient receptor potential melastatin 7 (TRPM7), a member of TRP melastatin subfamily, is a Ca 2+ -permeable nonselective cation channel 6-8 whose expression has been detected in VSMCs. 9,10Through Ca 2+ signals, TRPM7 channels participate in many physiological and pathophysiological processes, including directed cell migration, 11 cell adhesion, 12 anoxic neuronal death, 13 and transdifferentiation of cardiac fibroblast.14 Moreover, TRPM7 is essential for embryonic development, as evidenced by genetic ablation leading to embryonic lethality. 15,16 However, the functional role of TRPM7-mediated Ca 2+ signaling in the phenotypic switching of VSMCs has not been explored.VSMCs change their phenotype in response to various environmental cues, of which angiotensin II (Ang II) has been extensively studied. Ang II exerts multiple effects on vascular smooth muscle, including contraction of arteries under normal circumstances. Nevertheless, in certain forms of hypertension, persistent elevation of Ang II level gives rise to vascular remodeling, in which growth of VSMCs plays a pivotal role. 17,18 The majority of the studies both in vitro and in vivo have demonstrated the hypertrophic effects of Ang II in rat thoracic aortic VSMCs,19,20 which are most widely used. Nonetheless, O...

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“…The calculation of Zn 2+ concentrations using the binding constant suggests that the vesicles contain <0.1 nM free Zn 2+ under resting conditions. To rule out any possible effects of vesicular pH on the sensor's Zn 2+ affinity, we showed that neutralization of the vesicular lumen with NH 4 Cl did not increase FRET (Fig. S5B).…”

Section: Trpm7mentioning

confidence: 99%

TRPM7 senses oxidative stress to release Zn ²⁺ from unique intracellular vesicles

Abiria

Krapivinsky

Sah

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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103

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TRPM7 (transient receptor potential cation channel subfamily M member 7) regulates gene expression and stress-induced cytotoxicity and is required in early embryogenesis through organ development. Here, we show that the majority of TRPM7 is localized in abundant intracellular vesicles. These vesicles (M7Vs) are distinct from endosomes, lysosomes, and other familiar vesicles or organelles. , an ion channel and cytoplasmic kinase, is ubiquitously expressed and essential in early embryonic development (1-4) but also may mediate oxidative stress-induced anoxic neuronal death in adults (5, 6). As an ion channel, TRPM7 conducts Zn 2+ >Mg 2+ ∼ Ca 2+ and monovalent cations (7-10) and contributes to labile cytosolic and nuclear Zn 2+ concentrations (8). TRPM7's C-terminal kinase can phosphorylate multiple substrates (11-13) and is cleaved to release a proapoptotic, chromatin-modifying enzyme (8,14). Zn 2+ regulates TRPM7's kinase activity (11) and binding to transcription factors (8). It is a potent signal for many cellular processes previously related to TRPM7 function, including gene expression, mitosis, and cell survival, but is also proapoptotic at extreme concentrations (15)(16)(17)(18) Oxidative stress increases inward divalent ion permeation through TRPM7 (5, 9), whereas acute and chronic oxidative stress in culture (24-26) or during ischemia-reperfusion in vivo (27, 28) induces TRPM7 expression. The resulting increase in cytosolic Zn 2+ could result in toxic cytosolic concentrations (9). Conversely, reduction of TRPM7 expression protects animals from postischemia reperfusion (5), a condition typically accompanied by increased reactive oxygen species (ROS) and Zn 2+ release from intracellular stores (29). Physiological redox transitions required for stem cell differentiation and gene expression during embryonic development (30, 31) may also be sensed by TRPM7 and transduced via Zn -dependent signals (32). Because TRPM7 patch-clamp recording is limited to the plasma membrane, the assumption has been that TRPM7's main function is on the plasma membrane. However, we have previously shown that TRPM7 is also on intracellular membranes (33-35). Indeed, ROS activation of divalent ion influx through TRPM7 (5, 9) is reminiscent of ROS activation of TRPM2, which releases Ca 2+ and Zn 2+ from lysosomes (36,37 ] and ROS during development and injury.

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The channel kinase, TRPM7 , is required for early embryonic development

Cited by 155 publications

References 30 publications

TRPM7 regulates vascular endothelial cell adhesion and tube formation

TRPM7 regulates vascular endothelial cell adhesion and tube formation

Upregulation of TRPM7 Channels by Angiotensin II Triggers Phenotypic Switching of Vascular Smooth Muscle Cells of Ascending Aorta

TRPM7 senses oxidative stress to release Zn ²⁺ from unique intracellular vesicles

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The channel kinase, TRPM7 , is required for early embryonic development

Cited by 155 publications

References 30 publications

TRPM7 regulates vascular endothelial cell adhesion and tube formation

TRPM7 regulates vascular endothelial cell adhesion and tube formation

Upregulation of TRPM7 Channels by Angiotensin II Triggers Phenotypic Switching of Vascular Smooth Muscle Cells of Ascending Aorta

TRPM7 senses oxidative stress to release Zn 2+ from unique intracellular vesicles

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TRPM7 senses oxidative stress to release Zn ²⁺ from unique intracellular vesicles