Affinage

TRPM6

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

Length
2022 aa
Mass
231.7 kDa
Annotated
2026-06-14
17 papers in source corpus 8 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRPM6 is an apical Mg2+ channel that mediates active transcellular magnesium reabsorption in the renal distal convoluted tubule (DCT), and its dysfunction causes renal Mg2+ wasting and hypomagnesemia (PMID:17671655, PMID:17671646, PMID:18299299). Channel activity is set by both hormonal and electrical inputs: basolateral EGF binding to EGFR on DCT cells activates apical TRPM6, and a pro-EGF mutation that disrupts basolateral pro-EGF sorting fails to stimulate TRPM6, producing magnesium wasting (PMID:17671655, PMID:17671646, PMID:18299299), while the favorable luminal membrane potential required for Mg2+ entry is generated by the co-localized Kv1.1 (KCNA1) K+ channel, such that a dominant-negative Kv1.1 mutation abolishing K+ current causes autosomal dominant hypomagnesemia (PMID:19307729). TRPM6 abundance in the DCT depends on the segment's transcriptional and structural integrity: the DCT-enriched transcription factor Prox-1 maintains TRPM6 mRNA and protein expression (PMID:33200256), and loss of the NaCl co-transporter NCC drives DCT atrophy with secondary reduction of TRPM6 (PMID:31436795). Beyond the kidney, TRPM6 (in TRPM6/TRPM7 complexes) governs intracellular Mg2+ levels that regulate mesoderm and definitive endoderm differentiation of human embryonic stem cells (PMID:26705539).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2007 High

    Established that TRPM6 channel activity is not autonomous but is controlled by hormonal input, explaining a heritable form of magnesium wasting and a clinical drug toxicity.

    Evidence Positional cloning of a pro-EGF mutation in a human kindred plus basolateral trafficking assays, corroborated by cetuximab-induced hypomagnesemia

    PMID:17671646 PMID:17671655 PMID:18299299

    Open questions at the time
    • Molecular signaling steps linking EGFR activation to TRPM6 gating not resolved
    • Direct biochemical interaction between EGFR pathway components and TRPM6 not defined
  2. 2009 High

    Showed that TRPM6-mediated Mg2+ entry requires an electrical driving force, identifying Kv1.1 as the K+ channel that sets the luminal membrane potential.

    Evidence Positional cloning of a dominant-negative KCNA1 mutation, DCT co-localization immunofluorescence, and patch-clamp of wild-type versus N255D Kv1.1

    PMID:19307729

    Open questions at the time
    • Whether Kv1.1 and TRPM6 physically interact versus only co-localize is not established
    • Quantitative contribution of membrane potential to TRPM6 conductance not measured directly
  3. 2015 Medium

    Extended TRPM6 function beyond epithelial transport, demonstrating that TRPM6/TRPM7-controlled intracellular Mg2+ influences early human cell-fate decisions.

    Evidence Kinome screen, loss-of-function and pharmacological inhibition (Mesendogen) with intracellular Mg2+ readout in human ESCs

    PMID:26705539

    Open questions at the time
    • Relative contributions of TRPM6 versus TRPM7 to the Mg2+ phenotype not separated
    • Downstream effectors linking Mg2+ to differentiation programs unidentified
    • Inhibitor specificity for TRPM6 not fully defined
  4. 2019 Low

    Identified a post-transcriptional regulator of TRPM6, placing the channel within a miRNA-controlled axis in cardiac injury.

    Evidence Dual-luciferase reporter validation of miR-202-3p targeting the TRPM6 3'UTR plus in vivo rat ischemia-reperfusion manipulation

    PMID:30810438

    Open questions at the time
    • Direct targeting confirmed by luciferase, but downstream TGF-β1/Smads link rests on indirect in vivo readouts in a single lab
    • TRPM6 expression and role in cardiac tissue not independently confirmed
    • Mechanism connecting TRPM6 loss to pathway activation undefined
  5. 2020 Medium

    Distinguished transcriptional from structural control of renal TRPM6 abundance, showing Prox-1 maintains its expression while NCC-dependent DCT integrity sustains its protein levels.

    Evidence DCT-specific Prox-1 conditional knockout and NCC knockout mice with mRNA/protein quantification and longitudinal morphological phenotyping

    PMID:31436795 PMID:33200256

    Open questions at the time
    • Whether Prox-1 binds the TRPM6 promoter directly versus acting indirectly is not shown
    • TRPM6 reduction after NCC loss is secondary to DCT atrophy rather than a direct regulatory link
    • Single-lab findings for each regulator

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular mechanism by which EGFR signaling and membrane potential converge to gate TRPM6, and the direct effectors linking TRPM6-controlled Mg2+ to cell-fate decisions, remain unresolved.
  • No structural model of TRPM6 gating in the timeline
  • No reconstituted EGFR-to-TRPM6 signaling pathway
  • Direct downstream targets of TRPM6-regulated Mg2+ unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-382551 Transport of small molecules 2
Partners
KCNA1TRPM7

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 EGF acts as a magnesiotropic hormone that stimulates TRPM6-mediated Mg2+ reabsorption in the renal distal convoluted tubule (DCT): basolateral EGF binds EGFR on the basolateral membrane of DCT cells, activating the apical Mg2+ channel TRPM6. A missense mutation in pro-EGF that impairs basolateral sorting of pro-EGF prevents adequate EGFR stimulation, resulting in insufficient TRPM6 activation and renal Mg2+ wasting. Positional cloning of disease mutation in human kindred; functional studies showing impaired basolateral pro-EGF trafficking and consequent failure to activate TRPM6; clinical correlation with cetuximab-induced hypomagnesemia The Journal of clinical investigation High 17671646 17671655 18299299
2009 TRPM6 mediates apical Mg2+ entry in the DCT and its activity depends on a favorable luminal membrane potential generated by the Kv1.1 potassium channel (KCNA1). Kv1.1 co-localizes with TRPM6 along the luminal membrane of DCT cells; a dominant-negative N255D mutation in Kv1.1 that abolishes K+ channel function causes autosomal dominant hypomagnesemia, establishing that Kv1.1-generated membrane potential is required for TRPM6-mediated Mg2+ reabsorption. Positional cloning; immunofluorescence co-localization of Kv1.1 and TRPM6 in DCT; patch clamp analysis of wild-type and N255D mutant Kv1.1 in human kidney cell line demonstrating dominant-negative loss of K+ current The Journal of clinical investigation High 19307729
2020 The transcription factor Prox-1 in DCT cells is required for maintaining TRPM6 expression: DCT-specific deletion of Prox-1 in adult mice causes significant downregulation of TRPM6 (and NCC) at both mRNA and protein levels, leading to hypomagnesemia, without affecting DCT structure or growth. Conditional knockout mouse model (NCCcre:Prox-1flox/flox); plasma ion measurements; immunofluorescence and RT-PCR/western blot for TRPM6 and NCC protein and mRNA Pflugers Archiv : European journal of physiology Medium 33200256
2020 Loss of the NaCl co-transporter (NCC) leads to DCT atrophy, which is associated with a marked reduction in TRPM6 protein abundance in the DCT; hypomagnesemia appears as a late consequence of this DCT regression. NCC knockout mice studied at multiple postnatal time points; immunofluorescence for parvalbumin (DCT marker) and TRPM6; plasma ion measurements Nephrology, dialysis, transplantation Medium 31436795
2015 TRPM6 (as part of TRPM6/TRPM7 channel complexes) controls intracellular Mg2+ levels and thereby regulates mesoderm and definitive endoderm differentiation of human embryonic stem cells; a small molecule inhibitor (Mesendogen/MEG) identified by kinome screen targets TRPM6, reduces intracellular Mg2+, and enhances these differentiation fates. Kinome screen; loss-of-function experiments; intracellular Mg2+ measurements; pharmacological inhibition and Mg2+-withdrawal phenocopy experiments in hESCs Heliyon Medium 26705539
2019 miR-202-3p directly targets the TRPM6 3'UTR (validated by dual-luciferase reporter assay) and negatively regulates TRPM6 expression; miR-202-3p overexpression or TRPM6 knockdown activates the TGF-β1/Smads signaling pathway in a rat myocardial ischemia-reperfusion model. Dual-luciferase reporter gene assay; in vivo rat I/R model with miRNA mimics, inhibitors, and siRNAs; measurement of inflammatory factors, fibrosis, and apoptosis Cell cycle (Georgetown, Tex.) Low 30810438

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia. The Journal of clinical investigation 254 17671655
2009 A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia. The Journal of clinical investigation 111 19307729
2013 Elucidation of the distal convoluted tubule transcriptome identifies new candidate genes involved in renal Mg(2+) handling. American journal of physiology. Renal physiology 44 24089412
2011 Hypomagnesaemia and targeted anti-epidermal growth factor receptor (EGFR) agents. Targeted oncology 37 22113391
2019 Overexpression of microRNA-202-3p protects against myocardial ischemia-reperfusion injury through activation of TGF-β1/Smads signaling pathway by targeting TRPM6. Cell cycle (Georgetown, Tex.) 33 30810438
2021 Mg2+ Transporters in Digestive Cancers. Nutrients 32 33450887
2007 When EGF is offside, magnesium is wasted. The Journal of clinical investigation 27 17671646
2020 Loss of sodium chloride co-transporter impairs the outgrowth of the renal distal convoluted tubule during renal development. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 17 31436795
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
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 Integration analysis of metabolome and transcriptome reveals the effect of exogenous supplementation with mixtures of vitamins ADE, zinc, and selenium on follicular growth and granulosa cells molecular metabolism in donkeys (Equus asinus). Frontiers in veterinary science 6 36387403
2008 Renal magnification by EGF. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 5 18299299
2025 Hypomagnesemia With Metformin Use in Diabetes Mellitus: A Case and Narrative Review. Kidney medicine 2 40613016
2025 Mechanism of AGT-Mediated Magnesium Ion Uptake in Age-Related Olfactory Dysfunction. Discovery medicine 1 40485519
2026 Potential Factors of Diabetes in Gitelman Syndrome and the Choices of the Appropriate Hypoglycemic Drugs: A Literature Narrative Review. Current issues in molecular biology 0 41751411
2025 Naringin Mitigates PEDV-Induced Intestinal Damage in Suckling Piglets by Modulating Inflammatory, Antiviral, and Metabolic and Transport Pathways. Biomolecules 0 41594589
2021 Hypomagnesemia with Secondary Hypoparathyroidism and Hypocalcemia due to Novel Variants in the Transient Receptor Potential Cation Channel Subfamily M Member 6 ( TRPM6 ) Gene. Journal of pediatric genetics 0 38567178

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