Emerging roles of TRPM6/TRPM7 channel kinase signal transduction complexes

Chubanov, Vladimir; Schnitzler, Michael Mederos y; Wäring, Janine; Plank, Anne-Christine; Gudermann, Thomas

doi:10.1007/s00210-005-1056-4

Cited by 36 publications

(27 citation statements)

References 94 publications

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“…TRPM6 belongs to the melastatin-related group of the TRP ion channel family (11,12). Like other TRP channels, TRPM proteins contain six transmembrane helices (S1-S6) flanked by cytoplasmic N and C termini; TRPMs most likely function as tetrameric channel complexes (12). Hydrophobic segments located between the S5 and S6 helices of four channel subunits are thought to contribute to a channel pore.…”

Section: Mgmentioning

confidence: 99%

“…Supplementation with high Mg 2ϩ doses compensates for the Mg 2ϩ deficiency of HSH patients (3, 9, 10). TRPM6 belongs to the melastatin-related group of the TRP ion channel family (11,12). Like other TRP channels, TRPM proteins contain six transmembrane helices (S1-S6) flanked by cytoplasmic N and C termini; TRPMs most likely function as tetrameric channel complexes (12).…”

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confidence: 99%

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Hypomagnesemia with Secondary Hypocalcemia due to a Missense Mutation in the Putative Pore-forming Region of TRPM6

Chubanov

Schlingmann

Wäring

et al. 2007

Journal of Biological Chemistry

104

120

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Hypomagnesemia with secondary hypocalcemia is an autosomal recessive disorder caused by mutations in the TRPM6 gene. Current experimental evidence suggests that TRPM6 may function in a specific association with TRPM7 by means of heterooligomeric channel complex formation. Here, we report the identification and functional characterization of a new hypomagnesemia with secondary hypocalcemia missense mutation in TRPM6. The affected subject presented with profound hypomagnesemia and hypocalcemia caused by compound heterozygous mutation in the TRPM6 gene: 1208(؊1)G > A affecting the acceptor splice site preceding exon 11, and 3050C > G resulting in the amino acid change (P1017R) in the putative pore-forming region of TRPM6. To assess the functional consequences of the P1017R mutation, TRPM6 P1017R and wild-type TRPM6 were co-expressed with TRPM7 in Xenopus oocytes and HEK 293 cells, and currents were assessed by two-electrode voltage clamp and whole cell patch clamp measurements, respectively. Co-expression of wild-type TRPM6 and TRPM7 resulted in a significant increase in the amplitude of TRPM7-like currents. In contrast, TRPM6 P1017R suppressed TRPM7 channel activity. In line with these observations, TRPM7, containing the corresponding mutation P1040R, displayed a dominant-negative effect upon co-expression with wild-type TRPM7. Confocal microscopy and fluorescence resonance energy transfer recordings demonstrated that the P1017R mutation neither affects assembly of TRPM6 with TRPM7, nor co-trafficking of heteromultimeric channel complexes to the cell surface. We conclude that a functional defect in the putative pore of TRPM6/7 channel complexes is sufficient to impair body magnesium homeostasis. Mg2ϩ plays a vital role in virtually all cellular pathways as a cofactor of enzymes, an essential structural element of proteins and nucleic acids, and a modulator of receptors and ion channels (1-4). At present, the molecular mechanisms controlling wasting (3, 9, 10). Hypocalcemia results from a secondary insufficiency of the parathyroid glands in the presence of profound hypomagnesemia. Supplementation with high Mg 2ϩ doses compensates for the Mg 2ϩ deficiency of HSH patients (3, 9, 10). TRPM6 belongs to the melastatin-related group of the TRP ion channel family (11,12). Like other TRP channels, TRPM proteins contain six transmembrane helices (S1-S6) flanked by cytoplasmic N and C termini; TRPMs most likely function as tetrameric channel complexes (12). Hydrophobic segments located between the S5 and S6 helices of four channel subunits are thought to contribute to a channel pore. In contrast to other known ion channels, TRPM6 and its closest family member, TRPM7, display the unique structural feature of being cation channels fused to Ser/Thr kinase domains at their C termini (13).TRPM7 is a ubiquitously expressed protein, which is essential for Mg 2ϩ homeostasis. Disruption of the TRPM7 gene in DT40 chicken lymphocytes and the zebrafish Danio rerio, resulted in Mg 2ϩ deficiency (14, 15). Functional characterization of he...

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Section: Mgmentioning

confidence: 99%

mentioning

confidence: 99%

Hypomagnesemia with Secondary Hypocalcemia due to a Missense Mutation in the Putative Pore-forming Region of TRPM6

Chubanov

Schlingmann

Wäring

et al. 2007

Journal of Biological Chemistry

104

120

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“…Whereas TRPM6 and TRPM7 share a protein kinase domain at their C-termini, the function of the long C-terminal ends of TRPM1 and TRPM3 is unclear. Delineated from the chimeric structure of a pore-forming transmembrane domain and a putative C-terminal domain with enzymatic activity, TRPM6 and TRPM7 were described as chanzymes or channel kinases (Drennan and Ryazanov 2004;Chubanov et al 2005). Within the human kinome, both channel kinases can be classified as atypical alpha protein kinases, which have homologies with the elongation factor 2 kinase and the heart, lymphocyte and muscle alpha kinases (Manning et al 2002).…”

Section: Trpm1 and Trpm3mentioning

confidence: 99%

Function and pharmacology of TRPM cation channels

Harteneck

2005

Naunyn-Schmiedeberg's Arch Pharmacol

145

126

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The physiological function and cellular role of some members of the TRPM family are poorly understood and still mysterious. Melastatin, the founding member of the TRPM group, is the most prominent example of the mysteries involved in understanding TRP channel function. Melastatin or TRPM1 was first cloned in 1998 and since then it has been suggested that it functions as a tumor suppressor protein in melanocytes. On the other hand, TRPM8 and TRPA1 have been described as cold receptors, TRPM4 and TRPM5 as calcium-activated nonselective cation channels, TRPM6 and TRPM7 as magnesium-permeable and magnesium-modulated cation channels, TRPM2 as an ADPribose-activated channel of macrophages, and TRPM3 as a hypo-osmolarity-and sphingosine-activated channel. There are many unsolved questions and many studies have to be performed to understand the overall function of the TRPM family. In addition to electrophysiological recordings and biochemical characterization, the use of compounds modulating TRPM channel function has often been helpful to study TRPM channels in a cellular context. Therefore, the review will summarize the known functions, activation mechanisms, and pharmacological modulations of the TRPM channels.

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“…For instance, alternative 5Ј exons of the gene can be spliced to a common second exon, suggesting the TRPM6 promoter governs mRNA expression by means of alternative transcription start sites. 11,76 Furthermore, several isoforms encode TRPM6 kinases because the alternatively spliced transcripts lack exons coding for the transmembrane segment of the channel. 11,76 Functional consequences of the naturally occurring TRPM6 mutations include introduction of frame shifts, stop codons, or disruption of exon splice sites.…”

Section: Role Of Trpm6 Channels In Renal Magnesium Homeostasismentioning

confidence: 99%

“…11,76 Furthermore, several isoforms encode TRPM6 kinases because the alternatively spliced transcripts lack exons coding for the transmembrane segment of the channel. 11,76 Functional consequences of the naturally occurring TRPM6 mutations include introduction of frame shifts, stop codons, or disruption of exon splice sites. 66,77,78 Only five missense mutations have been identified so far (Figure 2A) 66,77,78 ; their impact on TRPM6 function is discussed next.…”

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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Emerging roles of TRPM6/TRPM7 channel kinase signal transduction complexes

Cited by 36 publications

References 94 publications

Hypomagnesemia with Secondary Hypocalcemia due to a Missense Mutation in the Putative Pore-forming Region of TRPM6

Hypomagnesemia with Secondary Hypocalcemia due to a Missense Mutation in the Putative Pore-forming Region of TRPM6

Function and pharmacology of TRPM cation channels

Renal TRPathies

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