TRPM6 | Transient Receptor Potential channels | IUPHAR/BPS Guide to PHARMACOLOGY

TRPM6

Target id: 498

Nomenclature: TRPM6

Family: Transient Receptor Potential channels, ChaK subfamily

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     TRPM6 has curated GtoImmuPdb data

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 2022 9q21.13 TRPM6 transient receptor potential cation channel subfamily M member 6 1,5,8
Mouse 6 1 2028 19 B Trpm6 transient receptor potential cation channel, subfamily M, member 6 7
Rat 6 1 2020 1q43 Trpm6 transient receptor potential cation channel, subfamily M, member 6
Previous and Unofficial Names
HOMG | HSH | hypomagnesemia, secondary hypocalcemia | Channel kinase 2 | ChaK2 | Melastatin-related TRP cation channel 6 | transient receptor potential cation channel
Database Links
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
TRPM7 1,3
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
Not determined
Functional Characteristics
γ= 40–87 pS; permeable to mono- and di-valent cations with a preference for divalents (Mg2+ > Ca2+; PCa/PNa = 6.9), conductance sequence Zn2+ > Ba2+ > Mg2+= Ca2+ = Mn2+ > Sr2+ > Cd2+> Ni2+; strong outward rectification abolished by removal of extracellular divalents, inhibited by intracellular Mg2+ (IC50 = 0.5 mM) and ATP
Ion Selectivity and Conductance
Species:  Human
Rank order:  Zn2+ > Ba2+ > Mg2+ > Ca2+ > Mn2+ > Sr2+ > Cd2+ > Ni2+ [83.6 pS]
References:  3
Other chemical activators (Human)
constitutively active, activated by reduction of intracellular Mg2+

Download all structure-activity data for this target as a CSV file

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
2-APB Hs Agonist 3.4 – 3.7 pEC50 - -120.0 – 100.0 3
pEC50 3.4 – 3.7 (EC50 3.8x10-4 – 2.05x10-4 M) Potentiation [3]
Holding voltage: -120.0 – 100.0 mV
intracellular Mg2+ Hs - - - - -
extracellular H+ Hs Potentiation - - - -
μM range
Activator Comments
TRPM6 is also activated by low pH [3].
Channel Blockers
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
ruthenium red Hs Antagonist - - 1x10-7 - 1x10-5 -120.0 – -20.0 7
Conc range: 1x10-7 - 1x10-5 M [7]
Holding voltage: -120.0 – -20.0 mV
ruthenium red Hs - 7.0 pIC50 - -120.0
pIC50 7.0 (IC50 1x10-7 M)
Holding voltage: -120.0 mV
Ca2+ Hs - 5.3 – 5.3 pIC50 - -
pIC50 5.3 – 5.3 (IC50 5.4x10-6 – 4.8x10-6 M) inward current mediated by monovalent cations is blocked
Mg2+ Hs Antagonist 3.3 pIC50 - 80.0 7
pIC50 3.3 [7]
Holding voltage: 80.0 mV
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 2,9

Key to terms and symbols Click column headers to sort
Target used in screen: TRPM6
Ligand Sp. Type Action Affinity Units
TG-100-115 Hs Inhibitor Inhibition 8.1 pKd
erlotinib Hs Inhibitor Inhibition <5.5 pKd
A-674563 Hs Inhibitor Inhibition <5.5 pKd
GSK690693 Hs Inhibitor Inhibition <5.5 pKd
ruboxistaurin Hs Inhibitor Inhibition <5.5 pKd
SB203580 Hs Inhibitor Inhibition <5.5 pKd
gefitinib Hs Inhibitor Inhibition <5.5 pKd
masitinib Hs Inhibitor Inhibition <5.5 pKd
crizotinib Hs Inhibitor Inhibition <5.5 pKd
linifanib Hs Inhibitor Inhibition <5.5 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
Expressed on mouse B cells [4].
Tissue Distribution
Kidney, colon.
Species:  Human
Technique:  Northern Blot
References:  8
Kidney, small intestine, colon.
Species:  Human
Technique:  RT-PCR
References:  5
Kidney, testes.
Species:  Human
Technique:  RT-PCR
References:  1
Distal convoluted tubule, small intestine.
Species:  Mouse
Technique:  Immunohistochemistry
References:  7
Functional Assays
Overexpression of mouse TRPM6 in HEK 293 cells increases intracellular Mg2+ levels.
Species:  Mouse
Tissue:  HEK 293 cells.
Response measured:  Fluorescence by MagFura2
References:  7
Co-expression of human TRPM6 and TRPM7 in HEK 293 cells increases Mn2+ entry.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Fluorescence quenching of Fura2.
References:  1
When co-expressed in HEK 293 cells, human TRPM6 can phosphorylate TRPM7, but not vice versa.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Phosphothreonine antibody.
References:  6
Physiological Functions
Possible role in intestinal Mg2+ uptake and renal Mg2+ reabsorption; mutation in hTRPM6 causes hypomagnesemia with secondary hypocalcemia.
Species:  Human
Tissue:  Intestine, kidney.
References:  5,8
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Trpm6tm1.1Rws Trpm6tm1.1Rws/Trpm6tm1.1Rws
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB/N
MGI:2675603  MP:0000913 abnormal brain development PMID: 19692351 
Trpm6tm1.1Rws Trpm6tm1.1Rws/Trpm6tm1.1Rws
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB/N
MGI:2675603  MP:0003935 abnormal craniofacial development PMID: 19692351 
Trpm6tm1.1Rws Trpm6tm1.1Rws/Trpm6tm1.1Rws
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB/N
MGI:2675603  MP:0003743 abnormal facial morphology PMID: 19692351 
Trpm6tm1.1Rws Trpm6tm1.1Rws/Trpm6tm1.1Rws
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB/N
MGI:2675603  MP:0003720 abnormal neural tube closure PMID: 19692351 
Trpm6tm1.1Rws Trpm6tm1.1Rws/Trpm6tm1.1Rws
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB/N
MGI:2675603  MP:0001919 abnormal reproductive system physiology PMID: 19692351 
Trpm6+|Trpm6tm1.1Rws Trpm6tm1.1Rws/Trpm6+
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB/N
MGI:2675603  MP:0010093 decreased circulating magnesium level PMID: 19692351 
Trpm6tm1.1Rws Trpm6tm1.1Rws/Trpm6tm1.1Rws
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB/N
MGI:2675603  MP:0004200 decreased fetal size PMID: 19692351 
Trpm6tm1.1Rws Trpm6tm1.1Rws/Trpm6tm1.1Rws
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB/N
MGI:2675603  MP:0009431 decreased fetal weight PMID: 19692351 
Trpm6tm1.1Rws Trpm6tm1.1Rws/Trpm6tm1.1Rws
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB/N
MGI:2675603  MP:0006207 embryonic lethality during organogenesis PMID: 19692351 
Trpm6tm1.1Rws Trpm6tm1.1Rws/Trpm6tm1.1Rws
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB/N
MGI:2675603  MP:0000914 exencephaly PMID: 19692351 
Trpm6tm1.1Rws Trpm6tm1.1Rws/Trpm6tm1.1Rws
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB/N
MGI:2675603  MP:0006208 lethality throughout fetal growth and development PMID: 19692351 
Trpm6tm1.1Rws Trpm6tm1.1Rws/Trpm6tm1.1Rws
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB/N
MGI:2675603  MP:0002082 postnatal lethality PMID: 19692351 
Trpm6tm1.1Rws Trpm6tm1.1Rws/Trpm6tm1.1Rws
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB/N
MGI:2675603  MP:0002083 premature death PMID: 19692351 
Trpm6+|Trpm6tm1.1Rws Trpm6tm1.1Rws/Trpm6+
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB/N
MGI:2675603  MP:0002083 premature death PMID: 19692351 
Trpm6tm1.1Rws Trpm6tm1.1Rws/Trpm6tm1.1Rws
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB/N
MGI:2675603  MP:0000445 short snout PMID: 19692351 
Trpm6tm1.1Rws Trpm6tm1.1Rws/Trpm6tm1.1Rws
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * FVB/N
MGI:2675603  MP:0005297 spina bifida occulta PMID: 19692351 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Primary hypomagnesemia with secondary hypocalcemia
Synonyms: Hypomagnesemia 1, intestinal [OMIM: 602014]
OMIM: 602014
Orphanet: ORPHA30924
Role: 
References:  5,8
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human S141L 5
Nonsense Human A56X Premature stop codon leading to a truncated protein 8
Nonsense Human S590X Premature stop codon leading to a truncated protein 5

References

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1. Chubanov V, Waldegger S, Mederos y Schnitzler M, Vitzthum H, Sassen MC, Seyberth HW, Konrad M, Gudermann T. (2004) Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia. Proc. Natl. Acad. Sci. U.S.A., 101 (9): 2894-9. [PMID:14976260]

2. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

3. Li M, Jiang J, Yue L. (2006) Functional characterization of homo- and heteromeric channel kinases TRPM6 and TRPM7. J. Gen. Physiol., 127 (5): 525-37. [PMID:16636202]

4. Parenti A, De Logu F, Geppetti P, Benemei S. (2016) What is the evidence for the role of TRP channels in inflammatory and immune cells?. Br. J. Pharmacol., 173 (6): 953-69. [PMID:26603538]

5. Schlingmann KP, Weber S, Peters M, Niemann Nejsum L, Vitzthum H, Klingel K, Kratz M, Haddad E, Ristoff E, Dinour D, Syrrou M, Nielsen S, Sassen M, Waldegger S, Seyberth HW, Konrad M. (2002) Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat. Genet., 31 (2): 166-70. [PMID:12032568]

6. Schmitz C, Dorovkov MV, Zhao X, Davenport BJ, Ryazanov AG, Perraud AL. (2005) The channel kinases TRPM6 and TRPM7 are functionally nonredundant. J. Biol. Chem., 280 (45): 37763-71. [PMID:16150690]

7. Voets T, Nilius B, Hoefs S, van der Kemp AW, Droogmans G, Bindels RJ, Hoenderop JG. (2004) TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J. Biol. Chem., 279 (1): 19-25. [PMID:14576148]

8. Walder RY, Landau D, Meyer P, Shalev H, Tsolia M, Borochowitz Z, Boettger MB, Beck GE, Englehardt RK, Carmi R, Sheffield VC. (2002) Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat. Genet., 31 (2): 171-4. [PMID:12032570]

9. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

Contributors

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How to cite this page

David E. Clapham, Bernd Nilius, Grzegorz Owsianik.
Transient Receptor Potential channels: TRPM6. Last modified on 31/10/2016. Accessed on 17/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=498.