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Vascular biology of magnesium and its transporters in hypertension

Magnesium Research. Volume 23, Numéro 4, 207-15, december 2010, Short report

DOI : 10.1684/mrh.2010.0222


Auteur(s) : Alvaro Yogi, Glaucia E Callera, Tayze T Antunes, Rita C Tostes, Rhian M Touyz , Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Canada, Medical School of Ribeirao Preto, University of Sao Paulo, Brazil.


Auteur(s) : Alvaro Yogi1, Glaucia E Callera1, Tayze T Antunes1, Rita C Tostes2, Rhian M Touyz1

1Kidney Research Center, Ottawa Hospital Research Institute, University of Ottawa, Canada
2Medical School of Ribeirao Preto, University of Sao Paulo, Brazil

An inverse association between body Mg2+ levels and blood pressure has been reported in epidemiological studies and hypotensive actions of dietary Mg2+ supplementation and hypertensive effects of Mg2+ deficiency have been demonstrated in animal models and in patients [1-8]. Molecular processes underlying this relationship between blood pressure and Mg2+ are unclear, but Mg2+ effects on the vasculature have been suggested to be important.

Magnesium is an essential cation involved in many essential physiological and biochemical processes regulating cardiovascular function, including contraction and dilation, growth and inflammation, production of vasoactive agents and protein and nucleic acid synthesis. Magnesium is critical for many enzymatic reactions, since all phosphate-dependent reactions have an obligatory need for Mg2+ [9, 10]. Magnesium also regulates ion channels and is a natural antagonist to Ca2+ [11, 12]. Intracellular Mg2+ is tightly regulated and since Mg2+ is a critical component in multiple biochemical reactions, a small change in [Mg2+]i could lead to significant effects on signaling pathways that regulate vascular functions [13, 14]. Despite the fact that Mg2+ is such an abundant cytosolic cation and that it is so important in biological processes, there is a paucity of information regarding the mechanisms whereby cells regulate Mg2+ transport across cell membranes. Transporters and exchangers that have been implicated in transcellular Mg2+ transport include the Na+/Mg2+ exchanger, Mg2+/Ca2+ exchanger and recently identified cation channels, including transient receptor potential melastatin 6 and 7 channels (TRPM6, TRPM7) [15-21]. The present review will discuss the importance of Mg2+ in vascular biology in hypertension and will focus on the transport systems that may play a role in the control of vascular magnesium homeostasis.

Magnesium, vessels and hypertension

Hypomagnesemia and decreased tissue Mg2+ levels have been reported in various models of experimental hypertension [22, 23]. Clinical studies examining Mg2+ status in hypertensive patients have shown, for the most part, some form of hypomagnesemia (serum and/or tissue) and an inverse association between blood pressure levels and serum Mg2+ [24, 25]. Low serum Mg2+ is a common finding in elderly patients with metabolic syndrome [26]. Some investigations failed to demonstrate hypomagnesemia or decreased cellular Mg2+ in hypertension [27], while others reported elevated levels of erythrocyte [Mg2+]i [28]. Hypertensive patients with low Mg2+ levels require a greater number of antihypertensive medications compared with normomagnesemic patients [29]. A recent meta-analysis of 44 human studies showed that magnesium supplements may enhance the effects of antihypertensive medications in mildly hypertensive patients [30] and those with diabetes [31, 32]. Hypertensive patients treated with 600 mg of magnesium pidolate daily, demonstrated a small but significant reduction in day and night blood pressure as assessed by ambulatory monitoring [33].

Large population-based studies have also demonstrated variable associations between serum magnesium and blood pressure. Data from the Framingham Heart Study offspring cohort, failed to demonstrate that low serum magnesium is a risk factor for developing hypertension or CVD in 3,531 middle-aged adult participants [34]. On the other hand hypomagnesemia was found to be one of the strongest predictors of gain in left ventricular mass following 5 years in subjects (n = 1,348) enrolled in the “Study of Health in Pomerania” [35]. Moreover data from the WHO-coordinated CARDIAC (Cardiovascular Diseases and Alimentary Comparison) Study (3960 individuals from 41 WHO-CARDIAC study populations) demonstrated that among 5 diet-related factors, namely total cholesterol, body mass index, sodium, magnesium and taurine to creatinine (Cr) ratio in 24-hour urine, both Taurine/Cr and Mg2+/Cr were inversely related to coronary heart disease mortalities in males and females, suggesting that higher intakes of taurine and Mg2+ are associated with significantly lower all cardiovascular risks [36]. Similar trends were observed for stroke in the Atherosclerosis Risk in Communities Study cohort (14,221 men and women aged 45-64 years). Higher serum magnesium levels were associated with lower prevalence of hypertension and diabetes mellitus at baseline, while the 15-year follow-up, revealed 577 ischemic strokes, with serum magnesium being inversely associated with ischemic stroke incidence [37].

Low magnesium intake and associated risk for hypertension may be particularly important in females, both during childhood as well as in postmenopausal women. Data from the National Heart, Lung, and Blood Institute Growth and Health Study that enrolled 2,368 girls (49% Caucasian, 51% African-American) aged 9 or 10 years, showed that a lower intake of magnesium, fiber, potassium and calcium, and higher intake of caffeine and calories were each associated with increased incidence of hypertension [38]. In the Women's Health Initiative Observational Study, 3,713 postmenopausal women aged 50-79 years were studied with respect to circulating markers of inflammation (hs-CRP, IL-6, TNF-α, ICAM-1, VCAM-1, and e-Selectin), and daily Mg2+ intake [39]. High magnesium intake was associated with lower concentrations of markers of systemic inflammation and endothelial dysfunction, suggesting an inverse association between body magnesium and inflammation and an endothelial protective effect of magnesium in postmenopausal women.

Magnesium influences blood pressure, in part, by regulating vascular tone and reactivity. When infused intravenously in stroke patients, magnesium induces a significant vasodilatory response with an associated decrease in blood pressure [40]. Magnesium pidolate (368 mg/day of Mg ion) administered for 1 month to elderly diabetic patients, was associated with a significant improvement of the post-ischemic endothelial-dependent flow-mediated dilation, indicating improved vascular function [40]. In experimental animals, increased levels of extracellular magnesium caused vasorelaxation, decreased vascular resistance and attenuated agonist-induced vasoconstriction [41-43], whereas decreased concentrations caused contraction, potentiated agonist-induced vasoreactivity and increased vascular tone and blood pressure [44, 45]. Magnesium also influences vascular tone by preventing oxidative stress and by regulating cell growth and apoptosis [46-52]. It attenuates the generation of reactive oxygen species and pro-inflammatory mediators [48, 49] and it regulates MAP kinases in vascular cells [50, 51]. In intact arteries and arterial endothelial and vascular smooth muscle cells, Mg2+ stimulates production of prostacyclins and nitric oxide (NO), which induce vasodilation [46, 47]. In venous endothelial cells, TRPM7 downregulation and associated decreased cellular magnesium are associated with increased NOS activity and increased NO production, which may promote vasorelaxation [53]. Increased NOS/NO in this context of reduced TRPM7-mediated Mg2+ transport, may relate more to TRPM7 kinase deficiency than to changes in magnesium status. For the most part, magnesium is considered to induce vasodilation, as further evidenced by findings that magnesium lithospermate B, which activates eNOS and ameliorates endothelial dysfunction in diabetes by enhancing vasodilation, additionally reduces oxidative stress [54].

Because of the importance of Mg2+ in modulating vascular function, cellular levels need to be tightly regulated. Specific transporters controlling Mg2+ efflux and influx in cardiovascular and renal cells have recently been identified [21, 55-59] (table 1), some of which may be altered in hypertension [60].
Table 1 Magnesium transporters, functional role and distribution ion the cardiovascular and renal systems.




Cardiovascular- renal distribution

Mitochondrial RNA splicing 2 protein


Mitochondrial Mg2+ influx

Inner mitochondria

Solute carrier family 41, member 1


General transporter for divalent cations

Heart, kidney

Solute carrier family 41, member 2


General transporter for divalent cations, but not Ca2+


Magnesium Transporter 1


Mg2+-specific transporter convoluted tubules


Ancient Conserved Domain Protein 2


General transporter for divalent cations, but not Ca2+

Kidney cortex

Transient receptor potential melastatin 6


Renal and gastrointestinal Mg2+ absorption

Kidney tubules Vessels

Transient receptor potential melastatin 7


Cell viability Cellular Mg2+ homeostasis

Kidney, heart Vessels


Paracellular Mg2+ and Ca2+ reabsorption in the thick ascending limb of loop of Henle


Cellular Mg homeostasis

Unlike our knowledge of other major cations, the mechanisms regulating cellular Mg2+ handling are poorly understood. More than 95% of Mg2+ is sequestrated by chelators or bound to other biomolecules, including phospholipids, ribosomes and phosphonucleotides (ATP, ADP) [9, 13]. Intracellular Mg2+ is maintained below the concentration predicted from the transmembrane electrochemical potential. This control is achieved through a balance of Mg2+ uptake, intracellular storage, and Mg2+ efflux mediated through specific Mg2+ transporters.

Mg2+ efflux occurs against the electrochemical gradient, therefore an energy-coupled mechanism for its extrusion must be present. Mg2+ efflux appears to be regulated by at least two pathways: the Na+-Mg2+ exchange driven by the Na+ gradient, and the Na+-independent “passive” Mg2+ transport via Mg2+-permeable channels [14]. Na+-dependent Mg2+ transport occurs mainly via the Na+/Mg2+ exchanger and has been demonstrated in many cell types, including vascular smooth muscle cells (VSMC) and cardiomyocytes [18, 21]. On the other hand, Na+-independent transport, demonstrated mainly in erythrocytes and hepatic cells, involves Ca2+ (Ca2+/Mg2+ exchanger), Mn2+ (Mn2+/Mg2+ antiporter) and Cl (Cl/Mg2+ co-transporter)-dependent mechanisms (18,21). Regulation of these exchangers remains unclear, although angiotensin II (Ang II), aldosterone, and other vasoactive agents have been shown to influence these transporters [7, 17].

Until recently little was known about protein transporters controlling transmembrane magnesium influx. A few Mg2+ transporters had been demonstrated, but only at the biophysical and functional levels. Recent advances in the field have now identified specific transmembrane Mg2+ transporters. The first mammalian Mg2+ transporter to be identified at the molecular level was Mrs2 (mitochondrial RNA splicing2), responsible for mitochondrial Mg2+ uptake [21]. Other proteins shown to regulate Mg2+ homeostasis include Mg2+ transporter subtype 1 (MagT1), the solute carrier (SLC) family 41 subtype 1 and 2 (SLC41A1, SLAC41A2, respectively) and the Ancient Conserved Domain Protein 2 (ACDP2). Microarray analysis showed that the NIPA1 and 2 genes, named for “nonimprinted in Prader-Willi/Angelman”, membrane Mg2+ transporters 1 and 2 (MMgT1 and 2 respectively) and Huntington interacting protein genes, HIP14 and HIP14L also encode a Mg2+ transporter (reviewed in 21). The exact physiological role of these novel Mg2+ transporters with respect to Mg2+ homeostasis still awaits clarification, but many of the identified mammalian Mg2+ transporters have been associated with congenital disorders encompassing a wide range of tissues, including intestine, kidney, brain, nervous system, and skin.

Analysis of different forms of human disorders characterized by low serum Mg2+ levels due to defective intestinal absorption and/or renal Mg2+ wasting led to the identification of a paracellular (between cells) magnesium transporter, paracellin-1 (claudin 16), a member of the claudin family of tight-junction proteins [55]. Paracellin-1 mutations are associated with a hereditary disease, hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), characterized by massive renal Mg2+ and Ca2+ wasting leading to end-stage renal disease. Genetic analyses of patients with primary hypomagnesemia and secondary hypocalcaemia (HSH), another Mg2+-wasting disorder, identified TRPM6 (and its homologue TRPM7) as a key component of epithelial Mg2+ reabsorption [56, 57]. The ubiquitously expressed TRPM7 was characterized functionally as a constitutively active ion channel permeable for divalent cations including Mg2+ and regulated by intracellular concentrations of Mg2+, magnesium-nucleotide complexes, and humoral factors [58, 59].

TRPM cation channels and magnesium

Whereas TRPM6 is expressed primarily in intestinal epithelia and kidney tubules, TRPM7 is ubiquitous, and is expressed in blood vessels, the heart, brain, lungs, liver, spleen and intestine [60-64]. We demonstrated that VSMC from rat and human resistance arteries possess functionally active TRPM7 cation channels [65]. TRPM7 has also been identified in vascular cells from pulmonary arteries [65].

TRPM7 is permeable to the dominant physiological divalent cations Ca2+ and Mg2+ and also to essential trace metal (Zn2+, Cu2+, Fe2+, Mn2+, Co2+, Ni2+) and toxic metal ions (Cd2+, Ba2+, Sr2+) [66-69]. Of the divalent cations, TRPM7 appears to be most selective for Mg2+ and is essential for cellular function [58, 59, 69, 70]. TRPM7 knockout cells, which undergo growth arrest and compromised viability, can be rescued by Mg2+ supplementation [70-73], although in HUVECs, TRPM7 downregulation by siRNA was associated with MAP kinase activation and cell growth [53]. TRPM6 and TRPM7 have the unique feature of possessing a transmembrane domain linked to an α-kinase domain at the C-terminus [75, 76]. Despite the high homology of TRPM6 and TRPM7, and although they are both implicated in Mg2+ distribution in the body, they have physiologically and pharmacologically distinct roles in Mg2+ homeostasis [76, 77]. Whereas TRPM6 appears to be involved mainly in regulating total body Mg2+ levels through the kidney and gastrointestinal tract [78, 79], TRPM7 may be more important in regulating intracellular Mg2+ homeostasis and [Mg2+]i [76, 79].

TRPM7, like TRPM6, is regulated by changes in cytosolic Mg2+ or Mg2+-ATP [80-82]. This is the reason why TRPM7 and TRPM6 were previously called MIC (magnesium inhibiting channel) or MagNuM (magnesium-nucleotide-regulated metal ion channel) [82]. Intracellular Mg2+ inhibits TRPM7, which may serve as a negative feedback mechanism to reduce Mg2+ uptake when the cell has sufficient Mg2+. Under conditions of low intracellular Mg2+, recovery from this inhibition may open the channel to normalize cytosolic Mg2+ levels. The modulatory effect of Mg2+ and Mg2+-ATP may be related to the protein kinase domain of the channel [82-84]. The dual ability of TRPM7 to act as a channel and at the same time as a kinase, suggests that this protein is involved in regulating both cellular Mg2+ status and intracellular signaling pathways. To date, three known TRPM7 kinase domain substrates have been identified, annexin-1, myosin IIA heavy chain and calpain [85-87], all important in controlling cell functions such as cell adhesion, cytoskeletal organization, cell migration, cell death and cell growth. Deletion of TRPM7 in mice is embryonic lethal and TRPM7-deficient mice (heterozygotes) reveal a defect in intestinal Mg2+ absorption, supporting the critical function of TRPM7 in normal magnesium homeostasis and in fundamental cellular processes [74].

Factors influencing TRPM7 expression and activity are still under investigation. Other than Mg2+ and Mg-ATP, the role of second messengers in TRPM7 regulation is unclear. PIP2 may inhibit TRPM7 channel activity [80, 88]. Some studies suggested that cAMP influences TRPM7 channel activity [89], whereas others failed to demonstrate that cAMP/cGMP signaling influences TRPM7 activity (90). TRPM7 binds directly to several PLC isoforms, including PLC and PLC [90], which may be important for G protein-coupled receptor activation of TRPM7. Humoral factors, including bradykinin, Ang II, aldosterone and estrogen [65, 90-92], and mechanical factors, such as shear stress and stretch [87, 92-95], which are involved in the regulation of vascular tone and structure, also modulate TRPM7. Bradykinin increases TRPM7 channel activity in N1E-115 cells [90]. In VSMC, Ang II and aldosterone modulate TRPM6 and TRPM7 expression and influence TRPM7-dependent Mg2+ transport [65]. Much research, especially in physiologically relevant systems and not in cell lines, is still needed to understand exactly how TRPM7 is regulated, what stimuli activate or inhibit TRPM7 activity, how intracellular signaling molecules regulate the channel and kinase domains, what the downstream signaling targets of TRPM7 kinase are and how TRPM7 influences cellular functional responses.

Mg2+ transporters in hypertension

Studies from our laboratory and those of others demonstrated that decreased [Mg2+]i in hypertension is associated with alterations in both Mg2+ efflux and influx. The Na+/Mg2+ antiport plays a major role in Mg2+ extrusion in cardiac, renal and VSMC and in hypertension, the Na+/Mg2+ antiporter function is altered [96-98]. This exchanger is inhibited by amiloride, quinine, imipramine and manganese [99]. In spontaneously hypertensive rats (SHR), amiloride and quinidine administration was associated with an increase in vascular [Mg2+]i and attenuation of the development of hypertension. In Ang II-induced hypertension in rats, inhibition of the Na+/Mg2+ antiporter resulted in reduced blood pressure, normalization of vascular and renal MAP kinase activity and improved vascular structure [100]. Other studies have also demonstrated alterations in Na+/Mg2+ exchanger activity in hypertension [96, 98, 101].

Altered Mg2+ influx in VSMC in SHR was associated with downregulation of vascular TRPM7, but not TRPM6 [102]. The mechansims underlying this are unclear. Similarly to what was reported in cell lines, we also found that TRPM7 and Mg2+ are critical for vascular cell viability, because TRPM7 knockdown with siRNA in VSMC resulted in reduced cell growth, which was restored upon Mg2+ supplementation [65]. Hence, aberrations in vascular TRPM7-regulated Mg2+ homeostasis in hypertension may contribute to altered vascular growth and contraction, important in vascular remodeling in hypertension [92, 103, 104].


At the vascular level, increased [Mg2+]i is associated with vasodilation, anti-inflammatory responses and reduced blood pressure. On the other hand, decreased [Mg2+]i is associated with endothelial dysfunction, increased reactivity, enhanced contractility, vascular remodeling and inflammation and elevated blood pressure. Vascular Na+/Mg2+ exchanger activity and TRPM7 expression/activity appear to be altered in experimental models of hypertension and may contribute to magnesium dysregulation and altered vascular function in hypertension. Since the recent identification and characterization of Mg2+-selective transporters, there has been enormous interest in the field. However, there is a paucity of information and much research is needed to clarify the exact mechanisms of magnesium homeostasis in the cardiovascular system and the implications of aberrant cellular magnesium transport in the pathogenesis of hypertension and other vascular diseases. The role for magnesium in the management of hypertension still awaits clarification.

Disclosure and financial support

Studies from the author's laboratory were supported by grant 57786 from the Canadian Institutes of Health Research (CIHR) and from the Heart and Stroke Foundation of Canada. Dr Touyz is supported through a Canada Research Chair/Canadian Foundation for Innovation award.

None of the authors has any conflict of interest to disclose.


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58 Nadler MJ, Hermosura MC, Inabe K, Perraud AL, Zhu Q, Stokes AJ, Kutosaki T, Kinet JP, Penner R, Scharenberg AM, Fleig A. LTRPC7 is a Mg ATP-regulated divalent cation channel required for cell viability. Nature 2001; 411: 590-5.

59 Runnels LW, Yue L, Clapham DE. TRP-PLIK, a bifunctional protein with kinase and ion channel activities. Science 2001; 291: 1043-7.

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62 Groenestege WM, Hoenderop JG, van den Heuvel L, Knoers N, Bindels RJ. The epithelial Mg2+ channel transient receptor potential melastatin 6 is regulated by dietary Mg2+ content and estrogens. J Am Soc Nephrol 2006; 17: 1035-43.

63 Fleig A, Penner R. The TRPM ion channel subfamily: molecular, biophysical and functional features. Trends Pharmacol Sci 2004; 25: 633-9.

64 Fonfria E, Murdock PR, Cusdin FS, Benham CD, Kelsell RE, McNulty S. Tissue distribution profiles of the human TRPM cation channel family. J Recept Signal Transduct Res 2006; 26: 159-78.

65 He Y, Yao G, Savoia C, Touyz RM. Transient receptor potential melastatin 7 ion channels regulate magnesium homeostasis in vascular smooth muscle cells: role of angiotensin II. Circ Res 2005; 96: 207-15.

66 Yang XR, Lin MJ, McIntosh LS, Sham JS. Functional expression of transient receptor potential melastatin- and vanilloid-related channels in pulmonary arterial and aortic smooth muscle. Am J Physiol Lung Cell Mol Physiol 2006; 290: L1267-L1276.

67 Beech DJ. Emerging functions of 10 types of TRP cationic channel in vascular smooth muscle. Clin Exp Pharmacol Physiol 2005; 32: 597-603.

68 Gwanyanya A, Amuzescu B, Zakharov SI, Macianskiene R, Sipido KR, Bolotina VM, Vereecke J, Mubagwa K. Magnesium-inhibited, TRPM6/7-like channel in cardiac myocytes: permeation of divalent cations and pH-mediated regulation. J Physiol 2004; 559: 761-76.

69 Nadler MJ, Hermosura MC, Inabe K, Perraud AL, Zhu Q, Stokes AJ, Kurosaki T, Kinet JP, Penner R, Scharenberg AM, Fleig A. LTRPC7 is a Mg.ATP-regulated divalent cation channel required for cell viability. Nature 2001; 411: 590-5.

70 Schmitz C, Perraud AL, Johnson CO, Inabe K, Smith MK, Penner R, Kurosaki T, Fleig A, Scharenberg AM. Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7. Cell 2003; 114: 191-200.

71 McNeill MS, Paulsen J, Bonde G, Burnight E, Hsu MY, Cornell RA. Cell Death of Melanophores in Zebrafish trpm7 Mutant Embryos Depends on Melanin Synthesis. J Invest Dermatol 2007; 127: 2020-30.

72 Aarts M, Iihara K, Wei WL, Xiong ZG, Arundine M, Cerwinski W, MacDonald JF, Tymianski M. A key role for TRPM7 channels in anoxic neuronal death. Cell 2003; 115: 863-77.

73 McNulty S, Fonfia E. The role of TRPM channels in cell death. Pflugers Arch 2005; 451: 235-42.

74 Ryazanova LV, Rondon LJ, Zierler S, Hu Z, Galli J, Yamaguchi TP, Mazur A, Fleig A, Ryazanov AG. TRPM7 is essential for Mg(2+) homeostasis in mammals. Nat Commun 2010; 1: 109-13.

75 Montell C. The TRP superfamily of cation channels. Sci STKE 2005; 2005: re3.

76 Schmitz C, Perraud AL, Fleig A, Scharenberg AM. Dual-function ion channel/protein kinases: novel components of vertebrate magnesium regulatory mechanisms. Pediatr Res 2004; 55: 734-7.

77 Li M, Jiang J, Yue L. Functional characterization of homo- and heteromeric channel kinases TRPM6 and TRPM7. J Gen Physiol 2006; 127: 525-37.

78 Chubanov V, Gudermann T, Schlingmann KP. Essential role for TRPM6 in epithelial magnesium transport and body magnesium homeostasis. Pflugers Arch 2005; 451: 228-34.

79 Elizondo MR, Budi EH, Parichy DM. trpm7 Regulation of in Vivo Cation Homeostasis and Kidney Function Involves Stanniocalcin 1 and fgf23. Endocrinology 2010; 151: 5700-9.

80 Gwanyanya A, Sipido KR, Vereecke J, Mubagwa K. ATP and PIP2 dependence of the magnesium-inhibited, TRPM7-like cation channel in cardiac myocytes. Am J Physiol Cell Physiol 2006; 291: C627-C635.

81 Penner R, Fleig A. The Mg2+ and Mg(2+)-nucleotide-regulated channel-kinase TRPM7. Handb Exp Pharmacol 2007; 179: 313-28.

82 Dietrich A, Chubanov V, Kalwa H, Rost BR, Gudermann T. Cation channels of the transient receptor potential superfamily: their role in physiological and pathophysiological processes of smooth muscle cells. Pharmacol Ther 2006; 112: 744-60.

83 Demeuse P, Penner R, Fleig A. TRPM7 channel is regulated by magnesium nucleotides via its kinase domain. J Gen Physiol 2006; 127: 421-34.

84 Schmitz C, Dorovkov MV, Zhao X, Davenport BJ, Ryazanov AG, Perraud AL. The channel kinases TRPM6 and TRPM7 are functionally nonredundant. J Biol Chem 2005; 280: 37763-71.

85 Dorovkov MV, Ryazanov AG. Phosphorylation of annexin I by TRPM7 channel-kinase. J Biol Chem 2004; 279: 50643-6.

86 Su LT, Agapito MA, Li M, Simonson WT, Huttenlocher A, Habas R, Yue L, Runnels LW. TRPM7 regulates cell adhesion by controlling the calcium-dependent protease calpain. J Biol Chem 2006; 281: 11260-70.

87 Clark K, Langeslag M, van Leeuwen B, Ran L, Ryazanov AG, Figdor CG, Moolenaar WH, Jalink K, van Leeuwen FN. TRPM7, a novel regulator of actomyosin contractility and cell adhesion. EMBO J 2006; 25: 290-301.

88 Runnels LW, Yue L, Clapham DE. The TRPM7 channel is inactivated by PIP(2) hydrolysis. Nat Cell Biol 2002; 4: 329-36.

89 Takezawa R, Schmitz C, Demeuse P, Scharenberg AM, Penner R, Fleig A. Receptor-mediated regulation of the TRPM7 channel through its endogenous protein kinase domain. Proc Natl Acad Sci USA 2004; 101: 6009-14.

90 Langeslag M, Clark K, Moolenaar WH, van Leeuwen FN, Jalink K. Activation of TRPM7 channels by phospholipase C-coupled receptor agonists. J Biol Chem 2007; 282: 232-6.

91 Groenestege WM, Hoenderop JG, van den Heuvel L, Knoers N, Bindels RJ. The epithelial Mg2+ channel transient receptor potential melastatin 6 is regulated by dietary Mg2+ content and estrogens. J Am Soc Nephrol 2006; 17: 1035-43.

92 Sontia B, Montezano AC, Paravicini T, Tabet F, Touyz RM. Downregulation of renal TRPM7 and increased inflammation and fibrosis in aldosterone-infused mice: effects of magnesium. Hypertension 2008; 51: 915-21.

93 Earley S. Vanilloid and melastatin transient receptor potential channels in vascular smooth muscle. Microcirculation 2010; 17: 237-49.

94 Numata T, Shimizu T, Okada Y. TRPM7 is a stretch- and swelling-activated cation channel involved in volume regulation in human epithelial cells. Am J Physiol Cell Physiol 2007; 292: C460-C467.

95 Oancea E, Wolfe JT, Clapham DE. Functional TRPM7 channels accumulate at the plasma membrane in response to fluid flow. Circ Res 2006; 98: 245-53.

96 Kisters K, Tokmak F, Kosch M, Hausberg M. Role of the Na+/Mg2+ exchanger in hypertension. Am J Hypertens 2003; 16: 95-6.

97 Touyz RM, Schiffrin EL. Angiotensin II and vasopressin modulate intracellular free magnesium in vascular smooth muscle cells through Na+-dependent protein kinase C pathways. J Biol Chem 1996; 271: 24353-8.

98 Picado MJ, de la Sierra A, Aguilera MT, Coca A, Urbano-Márquez A. Increased activity of the Mg2+/Na+ exchanger in red blood cells from essential hypertensive patients. Hypertension 1994; 23: 987-91.

99 Touyz RM, Schiffrin EL. Activation of the Na+/H+ exchanger modulates angiotensin II-stimulated Na+-dependent Mg2+ transport in vascular smooth muscle cells from spontaneously hypertensive rats. Hypertension 1999; 34: 442-9.

100 Touyz RM, Yao G. Inhibitors of Na+/Mg2+ exchange activity attenuate the development of hypertension in angiotensin II-induced hypertensive rats. J Hypertens 2003; 21: 337-44.

101 Ebel H, Gunther T. Na+/Mg2+ antiport in erythrocytes of spontaneously hypertensive rats: role of Mg2+ in the pathogenesis of hypertension. Magnes Res 2005; 18: 175-85.

102 Touyz RM, He Y, Montezano AC, Yao G, Chubanov V, Gudermann T, Callera GE. Differential regulation of transient receptor potential melastatin 6 and 7 cation channels by ANG II in vascular smooth muscle cells from spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 2006; 290: R73-R78.

103 Paravicini TM, Yogi A, Mazur A, Touyz RM. Dysregulation of vascular TRPM7 and annexin-1 is associated with endothelial dysfunction in inherited hypomagnesemia. Hypertension 2009; 53: 423-9.

104 Montezano AC, Zimmerman D, Yusuf H, Burger D, Chignalia AZ, Wadhera V, van Leeuwen FN, Touyz RM. Vascular smooth muscle cell differentiation to an osteogenic phenotype involves TRPM7 modulation by magnesium. Hypertension 2010; 56: 453-62.


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