Transient receptor potential melastatin 6 and 7 channels, magnesium transport, and vascular biology: implications in hypertension

Touyz, Rhian M.

doi:10.1152/ajpheart.00903.2007

Cited by 133 publications

(103 citation statements)

References 244 publications

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“…These comments refer to rapidly growing renal epithelial cells; some cell types, particularly neural and lymphocytic established and nonestablished, are more resilient to Mg 2ϩ deficiency. These may be more conducive to long-term studies (148,151,172).…”

Section: Strategy For Identifying Novel Mg 2؉ Transportersmentioning

confidence: 99%

“…Mg 2ϩ is required for the catalytic activity of numerous metalloenzymes and can also serve a purely structural role by stabilizing the conformation of certain Mg 2ϩ -and Ca 2ϩ -dependent domains, such as Ca 2ϩ -binding proteins and transcriptional regulatory proteins. Deficiency of this essential metal has been implicated in many diseases, ranging from hypertension, migraines, and asthma to osteoporosis and other bone disorders (119,151,172). Intracellular free Mg 2ϩ concentration is on the order of 0.5 mM, which is 1-2% of the total cellular Mg 2ϩ (21,109).…”

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confidence: 99%

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Molecular identification of ancient and modern mammalian magnesium transporters

Quamme

2010

American Journal of Physiology-Cell Physiology

169

182

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handling is poorly understood.The purpose of this review is to describe some of the recent insights into the identification and function of mammalian Mg 2ϩ transporters. There is a large body of physiological evidence for mammalian Mg 2ϩ transporters, which have only begun to be identified on the molecular level (11, 51,109,117,135,148,170). In particular, I will detail, at some length, the novel Mg 2ϩ transporters that have been identified over the last several years. These will be examined from the perspective of the established and more characterized mammalian Mg 2ϩ channels, mitochondrial Mrs2 and TRPM7/6. I will briefly review plant, bacterial, and yeast transporters as they relate to our newly identified mammalian Mg 2ϩ transporters, because some of these proteins share characteristics with the more ancient forms of transporters. The identification and characterization of plant, prokaryote, and yeast Mg 2ϩ transporters have been extensively reviewed elsewhere (35, 70, 73, 138).

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Section: Strategy For Identifying Novel Mg 2؉ Transportersmentioning

confidence: 99%

mentioning

confidence: 99%

Molecular identification of ancient and modern mammalian magnesium transporters

Quamme

2010

American Journal of Physiology-Cell Physiology

169

182

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Section: Magnesium (Mgmentioning

confidence: 99%

“…Mg 2ϩ deficiency results in small cell size and cell cycle arrest (11), as well as accelerated cell senescence (12), and intracellular Mg 2ϩ levels modulate the activity of many ion channels (13-18). In whole animals, hypomagnesemia results in hypocalcemia (19,20), and Mg 2ϩ deficiency has been correlated to hypertension (21,22 (42)(43)(44)46), has raised interest in putative Mg 2ϩ channels. TRPM6 mutations have been linked to the human genetic disease familial hypomagnesemia with secondary hypocalcemia (47,48).…”

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confidence: 99%

Mammalian MagT1 and TUSC3 are required for cellular magnesium uptake and vertebrate embryonic development

Zhou

Clapham²

2009

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

176

184

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Magnesium (Mg [Mg 2ϩ ] is Ϸ0.5-1 mM (2-5). The majority of Mg 2ϩ is bound to the major building blocks of the cell, such as proteins, phospholipids, nucleic acids, and especially ATP (6). Serum [Mg 2ϩ ] is maintained in a relatively narrow range (1-2 mM) in mammals (7), only slightly higher than the intracellular free [Mg 2ϩ ], making the reversal potential for Mg 2ϩ close to zero. Thus, the electrochemical gradient for Mg 2ϩ is normally into the cell due to the negative plasma membrane potential. Compared to [Ca 2ϩ ], free [Mg 2ϩ ] in the cytosol fluctuates much less dramatically with extracellular stimuli (8). Nevertheless, Mg 2ϩ plays a fundamentally important role in cellular processes. Mg 2ϩ serves as a major cofactor of ATP; Ͼ90% of cellular ATP is Mg-ATP (9). Therefore, it is not surprising that cell metabolism and many enzymatic activities are affected by Mg 2ϩ homeostasis (10). Mg 2ϩ deficiency results in small cell size and cell cycle arrest (11), as well as accelerated cell senescence (12), and intracellular Mg 2ϩ levels modulate the activity of many ion channels (13-18). In whole animals, hypomagnesemia results in hypocalcemia (19,20), and Mg 2ϩ deficiency has been correlated to hypertension (21,22 (42)(43)(44)46), has raised interest in putative Mg 2ϩ channels. TRPM6 mutations have been linked to the human genetic disease familial hypomagnesemia with secondary hypocalcemia (47,48). TRPM7 knockout in DT-40 avian lymphocytes exhibited a Mg 2ϩ deficiency phenotype and growth arrest (49). However, detailed studies of [Mg 2ϩ ] in tissues of TRPM7 Ϫ/Ϫ mice show that these channels play little direct role in Mg 2ϩ homeostasis (50). The extremely low inward conductance of the TRPM6/7 channels rather suggests that the affects of permeant Mg 2ϩ are confined to the immediate vicinity of the channel.In this report, we took advantage of the growth arrest phenotype of the S. cerevisiae Mg 2ϩ transporter mutant alr1⌬, and performed a complementary screen to search for potential human genes that could rescue the phenotype. We found that MagT1, and its homolog, TUSC3, support the growth of alr1⌬ yeast without Mg 2ϩ supplementation. We show that both genes are required for mammalian cellular Mg 2ϩ uptake and are crucial for zebrafish embryonic development. ResultsMagT1 and TUSC3 Complement the Yeast ALR1 Mg 2؉ Transporter.

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“…Other aspects of TRPM channels are addressed in a number of excellent review articles. 7,12,[57][58][59][60][61][62][63][64] A few years ago, two independent groups showed that loss-of-function mutations in the human TRPM6 gene are the molecular cause of HSH. 10,56 HSH is an autosomal recessive disease that manifests in early infancy with generalized convulsions or symptoms of increased neuromuscular excitability including muscle spasms and tet-any.…”

Section: Role Of Trpm6 Channels In Renal Magnesium Homeostasismentioning

confidence: 99%

Renal TRPathies

Dietrich¹,

Chubanov²,

Gudermann³

2010

Journal of the American Society of Nephrology

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One key function of the kidneys is the ultrafiltration of plasma by glomeruli to dispose of metabolic end products, excess electrolytes, and water. A vast array of ion channels and transporters are critical for filtration, secretion, and resorption of electrolytes to maintain homeostasis. In recent years, investigations have focused on several members of the large transient receptor potential (TRP) family of ion channels, because mutations in genes encoding members of three different TRP ion channel subfamilies have been linked to human kidney diseases. 1 Mutations in PKD1 (encoding TRPP1) and PKD2 (coding for TRPP2) occur at high frequency in individuals with autosomal dominant polycystic kidney disease. 2,3 The latter mutations and the pathophysiology of polycystic kidney disease are not discussed further in this overview because the topic has been covered by numerous insightful review articles. 4 -7 Missense and nonsense mutations in the gene coding for TRPC6 segregate with autosomal dominant FSGS, a kidney disease that leads to progressive renal failure. 8,9 Loss-of-function mutations in TRPM6 are also associated with hypomagnesemia with secondary hypocalcemia (HSH), a rare autosomal recessive disorder. 10 -12 The involvement of TRP channel mutations in hereditary kidney disease has shed new light on the molecular pathogenesis of renal failure and significantly enhanced our appreciation of the physiologic roles of TRP channels on tubular function. In this review, we focus exclusively on TRPC6 and TRPM6. TRPC6 AND PODOCYTE FUNCTIONTRPC6 is a nonselective cation channel and one of the seven members of the classical transient receptor potential (TRPC) family, which can be divided into subfamilies on the basis of amino acid similarity. Whereas TRPC1 and TRPC2 are almost unique, TRPC4 and TRPC5 share approximately 64% amino acid identity. TRPC3, TRPC6, and TRPC7 form a structural and functional subfamily displaying 65 to 78% identity at the amino acid level and share a common activator, diacylglycerol (DAG). 13 DAG is produced by phospholipase C isozymes activated after agonist binding to appropriate receptors, such as the interaction of angiotensin II (AngII) with AT 1 receptors.Like all TRPC family members, TRPC6 harbors an invariant sequence, the TRP box (containing the amino acid sequence EWKFAR), in its C-terminal tail as well as three ankyrin repeats in the N-terminus (Figure 1, A and B). The predicted transmembrane topology is similar to that of other TRP channels with intracellular N-and C-termini, six membrane-spanning helices (S1 through S6), and a presumed pore-forming loop (P) between S5 and S6 (Figure 1, A and B). As deduced from Northern blot analyses, TRPC6 channels are most prominently expressed in lung tissues, 14 where they ABSTRACTMany ion channels and transporters are involved in the filtration, secretion, and resorption of electrolytes by the kidney. In recent years, the superfamily of transient receptor potential (TRP) ion channels have received deserved attention because mutated TRP ch...

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Transient receptor potential melastatin 6 and 7 channels, magnesium transport, and vascular biology: implications in hypertension

Cited by 133 publications

References 244 publications

Molecular identification of ancient and modern mammalian magnesium transporters

Molecular identification of ancient and modern mammalian magnesium transporters

Mammalian MagT1 and TUSC3 are required for cellular magnesium uptake and vertebrate embryonic development

Renal TRPathies

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