Affinage

TRPM6

Transient receptor potential cation channel subfamily M member 6 · UniProt Q9BX84

Length
2022 aa
Mass
231.7 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRPM6 is a bifunctional channel-kinase that serves as the principal gatekeeper of transcellular Mg²⁺ absorption in the intestine and Mg²⁺ reabsorption in the renal distal convoluted tubule, with additional non-redundant roles in neural tube closure and circadian blood pressure regulation. The channel pore, whose divalent cation selectivity is determined by glutamate residues E1024 and E1029 in the selectivity filter, conducts Mg²⁺ and Ca²⁺ and is gated by intracellular Mg²⁺, PIP₂, and Mg·ATP; TRPM6 predominantly functions at the cell surface as a heteromer with TRPM7, which confers physiologically appropriate Mg·ATP insensitivity, while the fused C-terminal α-kinase domain autophosphorylates, transphosphorylates TRPM7, and scaffolds regulatory proteins including RACK1, REA, MsrB1, and uromodulin to modulate channel trafficking and gating (PMID:14576148, PMID:14976260, PMID:24385424, PMID:16636202, PMID:30139743). Channel surface abundance is dynamically controlled by EGF/Src/Rac1, insulin/PI3K/Rac1, and estrogen signaling pathways, and uromodulin stabilizes apical TRPM6 by impairing dynamin-dependent endocytosis (PMID:19073827, PMID:22733750, PMID:19329436, PMID:30139743). Loss-of-function mutations in TRPM6 cause autosomal-recessive hypomagnesemia with secondary hypocalcemia in humans, and complete knockout in mice causes embryonic lethality with neural tube defects (PMID:12032568, PMID:12032570, PMID:19692351).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2002 High

    Positional cloning resolved the genetic basis of hypomagnesemia with secondary hypocalcemia (HSH), establishing that TRPM6 mutations are causative and that the gene is expressed in intestinal and renal epithelia critical for Mg²⁺ homeostasis.

    Evidence Positional cloning and mutation analysis in HSH families, expression profiling in two independent studies

    PMID:12032568 PMID:12032570

    Open questions at the time
    • Channel properties unknown
    • Subcellular localization not resolved
    • Mechanism by which loss causes hypocalcemia unclear
  2. 2003 High

    Immunolocalization and electrophysiology established that TRPM6 resides at the apical membrane of DCT and intestinal brush border and forms a Mg²⁺/Ca²⁺-permeable cation channel with strong intracellular Mg²⁺ sensitivity, directly linking the genetic finding to a defined ion transport mechanism.

    Evidence Immunolocalization in kidney and intestine, whole-cell patch clamp of heterologously expressed TRPM6

    PMID:14576148

    Open questions at the time
    • Whether TRPM6 functions as a homomer or heteromer in vivo unknown
    • Pore determinants of selectivity unresolved
  3. 2004 High

    The discovery that TRPM6 requires TRPM7 for surface expression and forms TRPM6/TRPM7 heteromers—disrupted by the HSH-causing S141L mutation—provided a cell biological explanation for the disease and established heteromerization as the physiologically relevant channel configuration.

    Evidence Co-immunoprecipitation, confocal microscopy, and electrophysiology in HEK293 and Xenopus oocytes

    PMID:14976260

    Open questions at the time
    • Whether TRPM6 can form functional homomeric channels remained debated
    • Stoichiometry of heteromeric complex unknown
  4. 2005 High

    Functional non-redundancy of TRPM6 and TRPM7 was demonstrated: TRPM6 cannot complement TRPM7-deficient cells, and TRPM6 cross-phosphorylates TRPM7 but not vice versa, establishing an asymmetric kinase relationship.

    Evidence Genetic complementation in TRPM7-deficient DT40 cells, phosphothreonine-specific antibody detection

    PMID:16150690

    Open questions at the time
    • Functional consequences of TRPM6→TRPM7 transphosphorylation unknown
    • Sites of transphosphorylation not mapped
  5. 2006 High

    Biophysical characterization revealed that TRPM6 homomers have distinct conductance, pharmacology (2-APB activation), and pH sensitivity from TRPM7, while pore-region mutations (P1017R) act dominant-negatively on TRPM7, defining the channel pore as a critical functional locus.

    Evidence Single-channel recordings, pharmacological profiling, pore mutagenesis with electrophysiology and FRET in multiple expression systems

    PMID:16636202 PMID:17098283 PMID:17197439

    Open questions at the time
    • Structural basis of pore selectivity not resolved at atomic level
    • Relative contribution of homomers vs. heteromers in native tissue unknown
  6. 2007 High

    Mutagenesis of pore glutamates E1024 and E1029 defined the molecular determinants of divalent cation permeation and pH-dependent potentiation, converting the channel to monovalent selectivity upon neutralization.

    Evidence Site-directed mutagenesis with whole-cell patch clamp and ion substitution

    PMID:17599911

    Open questions at the time
    • No high-resolution pore structure available
    • How pore residues contribute to Mg²⁺ vs. Ca²⁺ discrimination at physiological levels not fully resolved
  7. 2008 High

    Multiple regulatory mechanisms converging on the α-kinase domain were uncovered: RACK1 inhibits channel activity through kinase-dependent T1851 autophosphorylation; massive autophosphorylation of a Ser/Thr-rich region controls substrate recognition; and myosin II heavy chains were identified as shared kinase substrates with TRPM7.

    Evidence Co-immunoprecipitation, patch clamp with siRNA and mutagenesis (RACK1); MS-based phosphomapping and deletion mutagenesis (autophosphorylation); in vitro kinase assay with MS (myosin substrates)

    PMID:18258429 PMID:18365021 PMID:18675813

    Open questions at the time
    • Physiological relevance of myosin phosphorylation by TRPM6 in epithelial Mg²⁺ transport not tested
    • How RACK1 inhibition integrates with other regulatory inputs unclear
  8. 2008 High

    EGF receptor signaling was shown to specifically increase TRPM6 surface abundance and channel activity via Src and Rac1, independent of kinase domain activity, establishing a hormonal pathway for regulated Mg²⁺ reabsorption.

    Evidence Patch clamp, FRAP, surface biotinylation with pharmacological and dominant-negative Rac1 constructs

    PMID:19073827

    Open questions at the time
    • Direct phosphorylation targets linking Rac1 to TRPM6 trafficking unknown
    • Whether EGF acts in vivo on DCT TRPM6 not directly tested
  9. 2009 High

    Two new regulatory axes were identified: REA inhibits TRPM6 in a kinase-dependent manner and is displaced by estradiol (linking sex hormones to Mg²⁺ handling), while Trpm6 knockout mice revealed embryonic lethality and neural tube defects, demonstrating developmental functions beyond ion homeostasis.

    Evidence Ras recruitment system, patch clamp, estradiol treatment (REA); global Trpm6 knockout mouse embryonic phenotyping (NTDs)

    PMID:19329436 PMID:19692351

    Open questions at the time
    • Mechanism by which TRPM6 regulates neural tube closure not identified
    • Whether estrogen-TRPM6 axis operates in vivo in kidney/intestine unresolved
  10. 2010 High

    MsrB1 was identified as a redox-responsive regulator that protects TRPM6 channel activity from oxidative inhibition by reducing Met1755, linking oxidative stress to Mg²⁺ transport.

    Evidence Ras recruitment system, patch clamp, M1755A mutagenesis, H₂O₂ treatment

    PMID:20584906

    Open questions at the time
    • Whether oxidative regulation of TRPM6 is physiologically relevant in DCT or intestine not tested in vivo
  11. 2011 High

    PIP₂ was established as an essential gating cofactor for TRPM6, with basic residues in the TRP domain mediating PIP₂-dependent activation, adding lipid signaling to the regulatory framework.

    Evidence Multiple PIP₂ depletion strategies (PLC, 5-phosphatase, Ci-VSP), patch clamp, TRP domain mutagenesis

    PMID:22180838

    Open questions at the time
    • Direct PIP₂ binding to TRPM6 not demonstrated by structural or biophysical methods
    • Contribution of PIP₂ regulation in heteromeric TRPM6/7 context not assessed
  12. 2012 High

    Insulin was shown to stimulate TRPM6 via PI3K/Rac1-mediated surface trafficking, and specific TRPM6 variants (V1393I, K1584E) that abolish insulin responsiveness were linked to gestational diabetes, connecting channel regulation to metabolic disease.

    Evidence Patch clamp, TIRF microscopy, PI3K/Rac1 inhibition, mutagenesis, clinical association

    PMID:22733750

    Open questions at the time
    • Causal relationship between TRPM6 variants and diabetes not established by Mendelian genetics
    • Identity of kinases phosphorylating T1391 and S1583 not determined
  13. 2014 High

    The physiological rationale for TRPM6/TRPM7 heteromerization was clarified: TRPM6 relieves TRPM7 from Mg·ATP inhibition through its kinase domain, while TRPM7 tunes TRPM6's extreme Mg²⁺ sensitivity, yielding constitutively active channels at physiological ion concentrations; separately, the kinase dimerization motif was shown to be essential for both kinase and channel activity.

    Evidence Patch clamp with kinase-dead mutants and intracellular ion manipulation; dimerization motif mutagenesis with peptide rescue and in vitro kinase assay

    PMID:24385424 PMID:24650431 PMID:24858416

    Open questions at the time
    • Stoichiometry and architecture of the heteromeric complex not structurally resolved
    • How kinase dimerization controls the channel pore conformationally is unknown
  14. 2017 High

    Studies in primary cells from TRPM6- and TRPM7-knockout mice confirmed that the heteromeric channel is the physiologically active species in epithelial cells, while mass spectrometry mapped transphosphorylation sites on TRPM7 and identified phosphomimetic substitutions that inactivate TRPM7 kinase, and Xenopus studies demonstrated TRPM6's non-redundant role in radial intercalation during neural tube closure.

    Evidence Patch clamp on primary knockout cells; MS phosphomapping with mutagenesis; Xenopus morpholino knockdown with live imaging

    PMID:28220887 PMID:28821869 PMID:29142255

    Open questions at the time
    • How TRPM6 governs cell intercalation movements mechanistically is unknown
    • Whether transphosphorylation of TRPM7 occurs in vivo in DCT
  15. 2018 High

    Uromodulin was identified as an extracellular stabilizer of apical TRPM6 that impairs dynamin-dependent endocytosis, with Umod⁻/⁻ mice showing reduced DCT TRPM6 and Mg²⁺ wasting, establishing a paracrine/extracellular regulatory axis.

    Evidence Co-immunoprecipitation, surface biotinylation, patch clamp, dynamin inhibition, Umod⁻/⁻ mouse model

    PMID:30139743

    Open questions at the time
    • Binding interface between uromodulin and TRPM6 extracellular domains not mapped
    • Whether uromodulin acts on heteromeric TRPM6/7 specifically not tested
  16. 2020 High

    Transcriptional control of TRPM6 was established: Prox-1 deletion in the DCT causes hypomagnesemia with loss of TRPM6 expression, identifying a critical upstream transcription factor.

    Evidence DCT-specific Prox-1 conditional knockout mice with RT-qPCR and immunohistochemistry

    PMID:33200256

    Open questions at the time
    • Whether Prox-1 directly binds the Trpm6 promoter not shown
    • Other transcription factors cooperating with Prox-1 not identified
  17. 2021 High

    Kidney-specific TRPM6 deletion revealed an unexpected role in circadian blood pressure regulation through control of renin secretion and β-adrenoreceptor expression in renin-secreting cells, extending TRPM6 function beyond Mg²⁺ transport.

    Evidence Kidney-specific conditional knockout mice, blood pressure telemetry, renin secretion assay, β-adrenoreceptor pharmacology

    PMID:34140503

    Open questions at the time
    • Mechanism linking DCT Mg²⁺ transport to renin-secreting cell β-adrenoreceptor expression unknown
    • Whether this is a direct or Mg²⁺-mediated effect not distinguished
  18. 2024 High

    Intestine-specific TRPM6 knockout with ²⁵Mg isotope tracing definitively proved that TRPM6 is essential for active intestinal Mg²⁺ absorption and cannot be compensated by other transporters despite compensatory upregulation of renal Trpm6, Trpm7, and Slc41a3.

    Evidence Intestine-specific Trpm6 knockout mice, ²⁵Mg²⁺ isotope absorption, RNA-seq

    PMID:39266724

    Open questions at the time
    • Whether compensatory renal upregulation is sufficient long-term not assessed
    • Role of intestinal TRPM6 in Ca²⁺ absorption not evaluated

Open questions

Synthesis pass · forward-looking unresolved questions
  • No high-resolution structure of TRPM6 (homomeric or heteromeric with TRPM7) has been reported, leaving the structural basis of heteromeric assembly, pore selectivity, kinase-channel coupling, and the mechanism by which TRPM6 controls neural tube closure and renin secretion unresolved.
  • No cryo-EM or crystal structure of full-length TRPM6 or TRPM6/7 heteromer
  • Mechanism linking TRPM6 to neural tube closure cell movements unknown
  • Signal from DCT TRPM6 to juxtaglomerular renin cells not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6 GO:0016740 transferase activity 5 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2
Partners
MSRB1P2X4RAC1RACK1REATRPM7UMOD
Complex memberships
TRPM6/TRPM7 heteromeric channel

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 TRPM6 mutations cause autosomal-recessive hypomagnesemia with secondary hypocalcemia (HSH); TRPM6 is expressed in intestinal epithelia and kidney tubules and is crucial for magnesium homeostasis, identified by positional candidate gene approach. Positional cloning, mutation analysis, expression studies Nature genetics High 12032568 12032570
2003 TRPM6 is specifically localized along the apical membrane of the renal distal convoluted tubule and brush-border membrane of the small intestine; heterologous expression of wild-type but not HSH-mutant TRPM6 induces a Mg2+- and Ca2+-permeable cation channel strongly regulated by intracellular Mg2+, with 5-fold higher affinity for Mg2+ than Ca2+, outward rectification, and voltage-dependent block by ruthenium red. Immunolocalization, heterologous expression, whole-cell patch clamp, ion substitution experiments The Journal of biological chemistry High 14576148
2004 TRPM6 alone is retained intracellularly when heterologously expressed, but specifically interacts with TRPM7 to form functional TRPM6/TRPM7 heteromeric channel complexes at the cell surface; the HSH-causing S141L missense mutation abolishes oligomeric assembly of TRPM6 with TRPM7, providing a cell biological explanation for the disease. Heterologous expression in HEK293 and Xenopus oocytes, co-immunoprecipitation, confocal microscopy, two-electrode voltage clamp, whole-cell patch clamp Proceedings of the National Academy of Sciences of the United States of America High 14976260
2006 TRPM6 forms functional homomeric channels with unique unitary conductance (~2-fold larger than TRPM7), distinct divalent cation permeability profile, unique pH sensitivity, and differential sensitivity to 2-APB (micromolar 2-APB maximally activates TRPM6 but inhibits TRPM7); TRPM6 also forms heteromeric TRPM6/7 complexes with intermediate pharmacological properties. Heterologous expression, whole-cell patch clamp, single-channel recordings, pharmacological profiling The Journal of general physiology High 16636202
2005 TRPM6 requires TRPM7 for surface expression in HEK-293 cells; TRPM6 cross-phosphorylates TRPM7 on threonine residues (detected by phosphothreonine-specific antibody) but TRPM7 does not phosphorylate TRPM6; TRPM7 deficiency in DT40 cells cannot be complemented by heterologously expressed TRPM6, demonstrating functional non-redundancy. Complementation assay in TRPM7-deficient DT40 B-cells, surface expression assay, phosphothreonine-specific antibody The Journal of biological chemistry High 16150690
2007 Two glutamate residues in the putative pore of TRPM6 (E1024 and E1029, corresponding to E1047 and E1052 in TRPM7) are key molecular determinants of Mg2+ and Ca2+ permeability and pH sensitivity; neutralization of E1024 (E1047 in TRPM7) largely abolished divalent permeation, converting the channel to monovalent selectivity and abolishing proton-mediated potentiation. Site-directed mutagenesis of pore residues, whole-cell patch clamp, ion substitution, pH manipulation The Journal of biological chemistry High 17599911
2006 A missense mutation P1017R in the putative pore-forming region of TRPM6 causes HSH; TRPM6(P1017R) suppresses TRPM7 channel activity in a dominant-negative manner when co-expressed, while not affecting TRPM6/TRPM7 assembly or co-trafficking to the cell surface, demonstrating that a pore-region functional defect alone is sufficient to impair body Mg2+ homeostasis. Two-electrode voltage clamp (Xenopus oocytes), whole-cell patch clamp (HEK293), confocal microscopy, FRET The Journal of biological chemistry High 17197439
2006 Neutralization of E1024 and D1031 in the TRPM6 selectivity filter (loop between TM5 and TM6, sequence GEIDVC) results in non-functional channels; E1029 neutralization increases conductance for Ba2+ and Zn2+ and alters pore diameter; I1030M reduces Ni2+ conductance — defining molecular determinants of TRPM6 cation permeation. Site-directed mutagenesis of pore residues, whole-cell patch clamp, permeability measurements Cell calcium High 17098283
2008 RACK1 (receptor for activated C-kinase 1) physically associates with the TRPM6 alpha-kinase domain and inhibits TRPM6 channel activity in a kinase activity-dependent manner; autophosphorylation of Thr1851 in the alpha-kinase domain is required for RACK1's inhibitory effect and is critical for Mg2+ sensitivity of TRPM6 activity; PKC activation by PMA abrogates RACK1 inhibition. Co-immunoprecipitation (Ras recruitment system), whole-cell patch clamp, siRNA knockdown, site-directed mutagenesis, PKC activation Current biology High 18258429
2008 TRPM6 and TRPM7 kinase domains undergo massive autophosphorylation (>30 mol/mol) predominantly in a Ser/Thr-rich region N-terminal to the catalytic domain; this autophosphorylation strongly increases the rate of substrate phosphorylation; deletion of the Ser/Thr-rich domain prevents substrate phosphorylation without affecting intrinsic catalytic activity, suggesting this domain controls substrate recognition. In vitro kinase assays, mass spectrometric phosphomapping, deletion mutagenesis, 32P autophosphorylation PloS one High 18365021
2008 TRPM6 and TRPM7 phosphorylate the assembly domain of myosin IIA, IIB and IIC on identical residues; phosphorylation of myosin IIA is restricted to the coiled-coil domain while TRPM6 and TRPM7 also phosphorylate the non-helical tails of myosin IIB and IIC; TRPM7 does not phosphorylate eEF-2, indicating substrate specificity distinct from other alpha-kinases. In vitro kinase assay, mass spectrometry FEBS letters High 18675813
2008 EGF receptor stimulation increases TRPM6 (but not TRPM7) channel current via Src family tyrosine kinases and downstream effector Rac1; activated Rac1 increases TRPM6 plasma membrane mobility (FRAP) and surface abundance, thereby augmenting channel activity; dominant-negative Rac1 abolishes EGF-mediated TRPM6 activation; the TRPM6 alpha-kinase domain is not required for this EGF-mediated activation. Whole-cell patch clamp, FRAP, surface biotinylation, dominant-negative and constitutively active Rac1 constructs, Src kinase inhibitors Journal of the American Society of Nephrology High 19073827
2009 REA (repressor of estrogen receptor activity) physically interacts with the 6th, 7th, and 8th beta-sheets of the TRPM6 alpha-kinase domain and inhibits TRPM6 (but not TRPM7) channel activity in a phosphorylation-dependent manner; TRPM6 kinase-dead mutant (K1804R) is not inhibited by REA despite maintained binding; PKC activation enhances REA inhibition; short-term 17β-estradiol treatment dissociates the REA-TRPM6 interaction and stimulates TRPM6-mediated current. Ras recruitment system (protein interaction), whole-cell patch clamp, co-immunoprecipitation, PKC activation, estradiol treatment The Journal of biological chemistry High 19329436
2010 MsrB1 (methionine sulfoxide reductase B1) interacts with the TRPM6 alpha-kinase domain (identified by Ras recruitment system); H2O2 decreases TRPM6 channel activity without affecting plasma membrane expression; co-expression of MsrB1 partially attenuates this inhibition; mutation of Met1755 to Ala reduces H2O2-mediated inhibition of TRPM6, indicating MsrB1 recovers TRPM6 activity by reducing oxidation of Met1755. Ras recruitment system, whole-cell patch clamp, surface biotinylation, site-directed mutagenesis, H2O2 treatment The Journal of biological chemistry High 20584906
2011 PIP2 (phosphatidylinositol-4,5-bisphosphate) is required for TRPM6 channel activation and Mg2+ influx; depletion of PIP2 by PLC-coupled M1-receptor stimulation, overexpressed 5-phosphatase, or voltage-sensitive phosphatase (Ci-VSP) potently inhibits TRPM6; neutralization of basic residues in the TRP domain reduces PIP2-dependent activation, implicating TRP domain residues in PIP2 interaction. Whole-cell patch clamp, TIRF, voltage-sensitive phosphatase (Ci-VSP), receptor-mediated PLC activation, 5-phosphatase overexpression, site-directed mutagenesis Scientific reports High 22180838
2012 Insulin stimulates TRPM6 channel activity via PI3-kinase and Rac1-mediated elevation of TRPM6 cell surface expression (assessed by TIRF microscopy and patch clamp); genetic variants TRPM6(V1393I) and TRPM6(K1584E) fail to respond to insulin stimulation, likely due to inability to phosphorylate TRPM6 Thr1391 and Ser1583; these variants are associated with higher glycated hemoglobin and gestational diabetes mellitus. Patch clamp, TIRF microscopy, site-directed mutagenesis, PI3K/Rac1 pathway inhibition Proceedings of the National Academy of Sciences of the United States of America High 22733750
2014 The TRPM6 kinase domain determines Mg·ATP sensitivity of TRPM7/M6 heteromeric channels: homomeric TRPM6 is highly sensitive to intracellular free Mg2+ (unlikely active at physiological levels); heteromeric TRPM7/TRPM6 channels have altered pharmacology and are independent of intracellular Mg·ATP, uncoupling channel activity from cellular energy status; disruption of TRPM6 kinase phosphorylation activity re-introduces Mg·ATP sensitivity to the heteromeric channel. Whole-cell patch clamp, co-expression, kinase-dead TRPM6 mutant, intracellular Mg2+ and Mg·ATP manipulation The Journal of biological chemistry High 24385424
2014 The dimerization motif (Leu1718/Leu1721) preceding the TRPM6 kinase domain and the dimerization pocket within the kinase domain are required for both kinase activity and ion channel activity; mutations disrupting this motif/pocket abolish kinase activity and greatly diminish channel activity independently of kinase activity; one disease-causing missense mutation (S1754N) near the dimerization motif abolishes kinase activity; a peptide encompassing the dimerization motif can restore kinase activity of dimerization motif mutants. Site-directed mutagenesis, in vitro kinase assay, patch clamp, peptide rescue experiment The Biochemical journal High 24650431
2014 TRPM6 kinase activity regulates TRPM7 intracellular trafficking and serine phosphorylation of TRPM7 (but TRPM7 kinase does not phosphorylate TRPM6 on serine); active TRPM6 kinase alters TRPM7 trafficking in HEK-293 and DT40 cells; co-expression of TRPM6 with intact kinase (but not kinase-dead mutant) inhibits TRPM7-dependent cell growth under hypomagnesic conditions. Phospho-specific antibodies, trafficking assays, genetic complementation in TRPM7-deficient DT40 B-cells, cell growth assay, kinase-dead mutant Cellular and molecular life sciences High 24858416
2017 mTRPM6 and mTRPM7 differentially regulate heteromeric mTRPM6/7 channels: mTRPM6 extreme sensitivity to Mg2+ is tuned by TRPM7 to higher concentrations, while mTRpm6 relieves mTRPM7 from tight Mg·ATP inhibition, resulting in high constitutive activity of the heteromeric complex at physiological Mg2+ and Mg·ATP levels in epithelial cells. Whole-cell patch clamp, comparative expression of mouse TRPM6 vs. TRPM7, primary cells from TRPM6- and TRPM7-deficient mice Scientific reports High 28821869
2017 Mass spectrometric analysis identified phosphorylation sites on TRPM6 including T1851 (autophosphorylation site in the kinase domain); TRPM6 transphosphorylates TRPM7 at multiple sites; phosphomimetic substitutions at TRPM7 S1777 (catalytic domain) and S1565 (exchange/dimerization domain) inactivate kinase activity through distinct mechanisms. Mass spectrometry, site-directed mutagenesis, in vitro kinase assay, molecular modeling Scientific reports High 28220887
2009 Trpm6 knockout mice (Trpm6-/-) exhibit embryonic mortality by E12.5 and neural tube defects (exencephaly and spina bifida occulta), demonstrating a non-redundant role of TRPM6 in neural tube closure during development, beyond its known role in Mg2+ homeostasis. Conditional knockout mouse model, embryonic phenotyping, dietary Mg2+ supplementation rescue attempts Human molecular genetics High 19692351
2017 Xenopus TRPM6 (XTRPM6) is expressed in lateral mesoderm and ectoderm at neurula stage; loss of XTRPM6 (but not XTRPM7) disrupts radial intercalation cell movements during neural tube closure, establishing a non-redundant role distinct from TRPM7; a zinc-influx assay showed TRPM6 can form functional channels in the absence of TRPM7. Xenopus laevis morpholino knockdown, in situ hybridization, live imaging of cell movements, zinc-influx assay Scientific reports High 29142255
2014 P2X4 receptor specifically inhibits TRPM6 (but not TRPM7) channel activity in a manner dependent on P2X4 channel activity; a P2X4 mutant with altered ATP sensitivity fails to inhibit TRPM6; P2X6 (non-functional in mammalian cells) does not inhibit TRPM6. Whole-cell patch clamp, co-expression, P2X4 mutants, RT-qPCR tissue expression Pflugers Archiv Medium 24413910
2018 Uromodulin (UMOD) physically interacts with TRPM6 from the extracellular space, enhances TRPM6 cell-surface abundance by impairing dynamin-dependent TRPM6 endocytosis, and increases TRPM6 current density; Umod-/- mice show decreased apical TRPM6 staining in the DCT and increased urinary Mg2+ excretion. Co-immunoprecipitation, surface biotinylation, whole-cell patch clamp, dynamin inhibition, Umod-/- mouse model, immunofluorescence The Journal of biological chemistry High 30139743
2021 Kidney-specific Trpm6 knockout mice show decreased blood pressure and loss of circadian blood pressure variation; renin secretion is not augmented in the active period and pharmacological β-adrenoreceptor activation fails to stimulate renin secretion; β-adrenoreceptor expression is decreased in renin-secreting cells of TRPM6-deficient kidneys, indicating TRPM6 in the DCT regulates renin secretion and circadian blood pressure. Kidney-specific conditional knockout mice, blood pressure telemetry, renin secretion assay, β-adrenoreceptor pharmacology Nature communications High 34140503
2019 Calmodulin (CaM) and S100A1 share a common binding site at the N-terminal TRPM6 domain (L520-R535); basic residues R526/R531/K532/R535 are critical for non-covalent interactions with both ligands; CaM and S100A1 bind via different mechanisms despite sharing the same domain. Biophysical methods (fluorescence, CD), molecular modelling, site-directed mutagenesis of N-terminal domain International journal of molecular sciences Medium 31505788
2015 Flavaglines (natural and synthetic compounds targeting prohibitins) stimulate TRPM6 channel activity ~2-fold at nanomolar concentrations; stimulatory effect requires the presence of the TRPM6 alpha-kinase domain but not its phosphotransferase activity; TRPM6 variants with impaired insulin sensitivity (V1393I and K1584E) are not sensitive to flavagline stimulation, suggesting they act via the insulin receptor signaling pathway. Whole-cell patch clamp, kinase domain deletion/mutation, pharmacological flavagline treatment PloS one Medium 25774985
2022 Iloperidone and ifenprodil selectively inhibit TRPM6 channel activity (IC50 0.73 and 3.33 µM respectively) without affecting TRPM7; VER155008 selectively suppresses TRPM7 (IC50 0.11 µM) without affecting TRPM6; effects confirmed on endogenous channels in native mouse and human cell models. Patch clamp, Ca2+ imaging, pharmacological analysis in native cell models Cell calcium High 36030694
2022 The nuclear receptor FXR (farnesoid X receptor) directly controls transcription of intestinal Trpm6 by binding an inverted repeat 1 (IR1) response element in an intronic FXR binding peak as a FXR-RXRα heterodimer; intestinal FXR is required for basal and GW4064-induced Trpm6 expression in mice. FXR ChIP-seq analysis, reporter assay with IR1 response element, FXR-knockout mice, GW4064 (FXR agonist) treatment, RT-qPCR International journal of molecular sciences Medium 35216094
2020 Deletion of transcription factor Prox-1 specifically in the DCT causes hypomagnesemia with profound downregulation of TRPM6 and NCC at both mRNA and protein levels, establishing Prox-1 as a transcriptional regulator of TRPM6 expression in the adult kidney. DCT-specific conditional knockout mice (NCCcre:Prox-1flox/flox), RT-qPCR, immunohistochemistry, Western blot, plasma electrolyte measurements Pflugers Archiv High 33200256
2024 Intestine-specific TRPM6 knockout (Vill1-TRPM6-/-) mice show significantly lower 25Mg2+ absorption, lower serum Mg2+ levels, and lower urinary Mg2+ excretion compared to controls; compensatory upregulation of renal Slc41a3, Trpm6, and Trpm7 gene expression is observed, demonstrating that intestinal TRPM6 is essential for Mg2+ absorption in the intestine. Intestine-specific conditional knockout mice, 25Mg2+ isotope absorption assay, RNA sequencing, RT-qPCR Pflugers Archiv High 39266724

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nature genetics 564 12032568
2003 TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. The Journal of biological chemistry 465 14576148
2002 Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nature genetics 403 12032570
2006 Functional characterization of homo- and heteromeric channel kinases TRPM6 and TRPM7. The Journal of general physiology 318 16636202
2004 Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia. Proceedings of the National Academy of Sciences of the United States of America 284 14976260
2007 TRPM6 and TRPM7--Gatekeepers of human magnesium metabolism. Biochimica et biophysica acta 209 17481860
2007 Molecular determinants of Mg2+ and Ca2+ permeability and pH sensitivity in TRPM6 and TRPM7. The Journal of biological chemistry 164 17599911
2005 The channel kinases TRPM6 and TRPM7 are functionally nonredundant. The Journal of biological chemistry 147 16150690
2008 EGF increases TRPM6 activity and surface expression. Journal of the American Society of Nephrology : JASN 133 19073827
2005 Novel TRPM6 mutations in 21 families with primary hypomagnesemia and secondary hypocalcemia. Journal of the American Society of Nephrology : JASN 122 16107578
2012 Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy. Proceedings of the National Academy of Sciences of the United States of America 118 22733750
2008 Massive autophosphorylation of the Ser/Thr-rich domain controls protein kinase activity of TRPM6 and TRPM7. PloS one 83 18365021
2006 Hypomagnesemia with secondary hypocalcemia due to a missense mutation in the putative pore-forming region of TRPM6. The Journal of biological chemistry 80 17197439
2005 Essential role for TRPM6 in epithelial magnesium transport and body magnesium homeostasis. Pflugers Archiv : European journal of physiology 79 16075242
2011 Phosphatidylinositol 4,5-bisphosphate (PIP(2)) controls magnesium gatekeeper TRPM6 activity. Scientific reports 77 22180838
2004 Magnesium-inhibited, TRPM6/7-like channel in cardiac myocytes: permeation of divalent cations and pH-mediated regulation. The Journal of physiology 76 15272039
2009 Mice defective in Trpm6 show embryonic mortality and neural tube defects. Human molecular genetics 75 19692351
2008 The alpha-kinases TRPM6 and TRPM7, but not eEF-2 kinase, phosphorylate the assembly domain of myosin IIA, IIB and IIC. FEBS letters 75 18675813
2014 The TRPM6 kinase domain determines the Mg·ATP sensitivity of TRPM7/M6 heteromeric ion channels. The Journal of biological chemistry 71 24385424
2017 TRPM6 and TRPM7 differentially contribute to the relief of heteromeric TRPM6/7 channels from inhibition by cytosolic Mg2+ and Mg·ATP. Scientific reports 70 28821869
2010 Methionine sulfoxide reductase B1 (MsrB1) recovers TRPM6 channel activity during oxidative stress. The Journal of biological chemistry 69 20584906
2011 TRPM6 and TRPM7: A Mul-TRP-PLIK-cation of channel functions. Current pharmaceutical biotechnology 64 20932259
2006 Molecular determinants of permeation through the cation channel TRPM6. Cell calcium 62 17098283
2009 Common genetic variants of the ion channel transient receptor potential membrane melastatin 6 and 7 (TRPM6 and TRPM7), magnesium intake, and risk of type 2 diabetes in women. BMC medical genetics 60 19149903
2008 Relationship between low magnesium status and TRPM6 expression in the kidney and large intestine. American journal of physiology. Regulatory, integrative and comparative physiology 59 18385471
2009 Regulation of the epithelial Mg2+ channel TRPM6 by estrogen and the associated repressor protein of estrogen receptor activity (REA). The Journal of biological chemistry 57 19329436
2013 New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia. European journal of human genetics : EJHG 51 23942199
2013 Omeprazole enhances the colonic expression of the Mg(2+) transporter TRPM6. Pflugers Archiv : European journal of physiology 50 23756852
2008 RACK1 inhibits TRPM6 activity via phosphorylation of the fused alpha-kinase domain. Current biology : CB 48 18258429
2018 Uromodulin regulates renal magnesium homeostasis through the ion channel transient receptor potential melastatin 6 (TRPM6). The Journal of biological chemistry 47 30139743
2018 TRPM6 is Essential for Magnesium Uptake and Epithelial Cell Function in the Colon. Nutrients 46 29912157
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2013 The TRPM6/EGF pathway is downregulated in a rat model of cisplatin nephrotoxicity. PloS one 43 23457647
2008 TRPM6 expression and cell proliferation are up-regulated by phosphorylation of ERK1/2 in renal epithelial cells. Biochemical and biophysical research communications 40 18339311
2005 Purification and characterization of an alkaline cellulase from a newly isolated alkalophilic Bacillus sp. HSH-810. Biotechnology letters 40 15834791
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2014 N-Myc-induced up-regulation of TRPM6/TRPM7 channels promotes neuroblastoma cell proliferation. Oncotarget 32 25277194
2011 Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment. American journal of physiology. Renal physiology 31 21653632
2007 Down-regulation of TRPM6-mediated magnesium influx by cyclosporin A. Naunyn-Schmiedeberg's archives of pharmacology 31 18026717
2014 P2X4 receptor regulation of transient receptor potential melastatin type 6 (TRPM6) Mg2+ channels. Pflugers Archiv : European journal of physiology 29 24413910
2011 Clinical and molecular characterization of Turkish patients with familial hypomagnesaemia: novel mutations in TRPM6 and CLDN16 genes. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 28 21669885
2010 Up-regulation of TRPM6 transcriptional activity by AP-1 in renal epithelial cells. Journal of cellular physiology 27 19937979
2017 Mass Spectrometric Analysis of TRPM6 and TRPM7 Phosphorylation Reveals Regulatory Mechanisms of the Channel-Kinases. Scientific reports 26 28220887
2017 Salvianolic acid B protects against acute lung injury by decreasing TRPM6 and TRPM7 expressions in a rat model of sepsis. Journal of cellular biochemistry 26 28636082
2014 TRPM6 kinase activity regulates TRPM7 trafficking and inhibits cellular growth under hypomagnesic conditions. Cellular and molecular life sciences : CMLS 25 24858416
2010 Modulation of TRPM6 and Na(+)/Mg(2+) exchange in mammary epithelial cells in response to variations of magnesium availability. Journal of cellular physiology 25 19890837
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2019 Magnesium Extravaganza: A Critical Compendium of Current Research into Cellular Mg2+ Transporters Other than TRPM6/7. Reviews of physiology, biochemistry and pharmacology 23 30406297
2015 Hypomagnesemia and functional hypoparathyroidism due to novel mutations in the Mg-channel TRPM6. Endocrine connections 22 26273099
2013 Novel TRPM6 mutations in familial hypomagnesemia with secondary hypocalcemia. American journal of nephrology 22 23689795
2022 Pharmacological agents selectively acting on the channel moieties of TRPM6 and TRPM7. Cell calcium 21 36030694
2015 The Different Roles of The Channel-Kinases TRPM6 and TRPM7. Current medicinal chemistry 21 26179995
2015 Increased TRPM6 expression in atrial fibrillation patients contribute to atrial fibrosis. Experimental and molecular pathology 20 25796343
2019 Increased risk of post-stroke epilepsy in Chinese patients with a TRPM6 polymorphism. Neurological research 19 30739590
2012 Increased expression of renal TRPM6 compensates for Mg(2+) wasting during furosemide treatment. Clinical kidney journal 18 26069797
2008 Insight into the molecular regulation of the epithelial magnesium channel TRPM6. Current opinion in nephrology and hypertension 18 18660673
2015 Differential mRNA expression and glucocorticoid-mediated regulation of TRPM6 and TRPM7 in the heart and kidney throughout murine pregnancy and development. PloS one 16 25692682
2015 Genetic loci for serum magnesium among African-Americans and gene-environment interaction at MUC1 and TRPM6 in European-Americans: the Atherosclerosis Risk in Communities (ARIC) study. BMC genetics 16 26058915
2008 Dietary inulin in mice stimulates Mg2+ absorption and modulates TRPM6 and TRPM7 expression in large intestine and kidney. Magnesium research 16 19271420
2021 Importance of the renal ion channel TRPM6 in the circadian secretion of renin to raise blood pressure. Nature communications 15 34140503
2014 Kinase and channel activity of TRPM6 are co-ordinated by a dimerization motif and pocket interaction. The Biochemical journal 14 24650431
2014 New TRPM6 mutation and management of hypomagnesaemia with secondary hypocalcaemia. Brain & development 14 24985022
2020 Metformin regulates TRPM6, a potential explanation for magnesium imbalance in type 2 diabetes patients. Canadian journal of physiology and pharmacology 13 32017603
2020 Magnesium Absorption in Intestinal Cells: Evidence of Cross-Talk between EGF and TRPM6 and Novel Implications for Cetuximab Therapy. Nutrients 13 33114586
2008 A case of hypomagnesemia with secondary hypocalcemia caused by Trpm6 gene mutation. Indian journal of pediatrics 13 18759094
2020 TRPM6 and TRPM7: Novel players in cell intercalation during vertebrate embryonic development. Developmental dynamics : an official publication of the American Association of Anatomists 12 32315468
2020 Deletion of the transcription factor Prox-1 specifically in the renal distal convoluted tubule causes hypomagnesemia via reduced expression of TRPM6 and NCC. Pflugers Archiv : European journal of physiology 12 33200256
2012 Resolving basal ganglia calcification in hereditary hypomagnesemia with secondary hypocalcemia due to a novel TRPM6 gene mutation. Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia 12 22982920
2010 Gene variation of the transient receptor potential cation channel, subfamily M, members 6 (TRPM6) and 7 (TRPM7), and type 2 diabetes mellitus: a case-control study. Translational research : the journal of laboratory and clinical medicine 12 20875900
2021 Evidence for the expression of TRPM6 and TRPM7 in cardiomyocytes from all four chamber walls of the human heart. Scientific reports 11 34326388
2019 TRPM6 N-Terminal CaM- and S100A1-Binding Domains. International journal of molecular sciences 11 31505788
2015 Flavaglines Stimulate Transient Receptor Potential Melastatin Type 6 (TRPM6) Channel Activity. PloS one 11 25774985
2008 Long-term follow-up of a patient with primary hypomagnesaemia and secondary hypocalcaemia due to a novel TRPM6 mutation. European journal of pediatrics 11 18548273
2006 Genetic background of HSH in three Polish families and a patient with an X;9 translocation. European journal of human genetics : EJHG 11 16267500
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2016 Expression of the TRPM6 in mouse placental trophoblasts; potential role in maternal-fetal calcium transport. The journal of physiological sciences : JPS 10 27043350
2022 Detection of TRPM6 and TRPM7 Proteins in Normal and Diseased Cardiac Atrial Tissue and Isolated Cardiomyocytes. International journal of molecular sciences 9 36499188
2021 Modulation of the Cardiac Myocyte Action Potential by the Magnesium-Sensitive TRPM6 and TRPM7-like Current. International journal of molecular sciences 9 34445449
2017 Effect of oral magnesium supplementation on the transcription of TRPM6, TRPM7, and SLC41A1 in individuals newly diagnosed of pre-hypertension. A randomized, double-blind, placebo-controlled trial. Magnesium research 9 29256407
2016 Magnesium-permeable TRPM6 polymorphisms in patients with meningomyelocele. SpringerPlus 9 27757375
2015 Mesendogen, a novel inhibitor of TRPM6, promotes mesoderm and definitive endoderm differentiation of human embryonic stem cells through alteration of magnesium homeostasis. Heliyon 9 26705539
2022 Transcriptional Control of Trpm6 by the Nuclear Receptor FXR. International journal of molecular sciences 7 35216094
2022 Case Report: Novel TRPM6 Mutations Cause Hereditary Hypomagnesemia With Secondary Hypocalcemia in a Chinese Family and a Literature Review. Frontiers in pediatrics 7 35903165
2017 A Nonredundant Role for the TRPM6 Channel in Neural Tube Closure. Scientific reports 7 29142255
1992 Nucleotide sequence of the genes for ribosomal proteins HS15 and HSH from Haloarcula marismortui: an archaeon-specific gene cluster. FEBS letters 7 1468549
2022 Mass spectrometric analysis of TRPM6 and TRPM7 from small intestine of omeprazole-induced hypomagnesemic rats. Frontiers in oncology 6 36110961
2021 Novel mutations in TRPM6 gene associated with primary hypomagnesemia with secondary hypocalcemia. Case report. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia 6 34012148
2014 Expressions of TRPM6 and TRPM7 and histopathological evaluation of tissues in ischemia reperfusion performed rats. Renal failure 6 24679001
2019 A pediatric case of hypomagnesemia 1 (HOMG1) caused by novel compound heterozygous mutations in TRPM6. Human genome variation 5 30911400
2018 TRPV6, TRPM6 and TRPM7 Do Not Contribute to Hair-Cell Mechanotransduction. Frontiers in cellular neuroscience 5 29515374
2015 Hypomagnesemia due to two novel TRPM6 mutations. Journal of pediatric endocrinology & metabolism : JPEM 5 26226117
2023 Magnesium Status, Genetic Variants of Magnesium-Related Ion Channel Transient Receptor Potential Membrane Melastatin 6 (TRPM6) and the Risk of Gestational Diabetes Mellitus in Chinese Pregnant Women: A Nested Case-Control Study. Molecular nutrition & food research 4 37759402
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2024 A Rare Case of Neonatal Hypomagnesemia with Secondary Hypocalcemia Caused by a Novel Homozygous TRPM6 Gene Variant. The American journal of case reports 3 38528672
2024 Characterization of intestine-specific TRPM6 knockout C57BL/6 J mice: effects of short-term omeprazole treatment. Pflugers Archiv : European journal of physiology 3 39266724
2010 Decreased renal mRNA expression of TRPM6 is associated with hypomagnesemia in C57BL/6 asthmatic mice. European review for medical and pharmacological sciences 3 21284342
2023 Intestinal hypomagnesemia in an Iranian patient with a novel TRPM6 variant: a case report and review of the literature. CEN case reports 2 36967423