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TRPM3

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Target not currently curated in GtoImmuPdb

Target id: 495

Nomenclature: TRPM3

Family: Transient Receptor Potential channels (TRP)

Contents:

Gene and Protein Information Click here for help
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 0 1732 9q21.12-q21.13 TRPM3 transient receptor potential cation channel subfamily M member 3 3,11,14
Mouse 6 1 1709 19 B Trpm3 transient receptor potential cation channel, subfamily M, member 3 17
Rat 6 0 1721 1q51 Trpm3 transient receptor potential cation channel, subfamily M, member 3
Previous and Unofficial Names Click here for help
LTRPC3 | MLSN2 | GON-2 | transient receptor potential cation channel
Database Links Click here for help
Alphafold Q9HCF6 (Hs)
CATH/Gene3D 1.20.5.1010
ChEMBL Target CHEMBL3559708 (Hs)
Ensembl Gene ENSG00000083067 (Hs), ENSMUSG00000052387 (Mm), ENSRNOG00000027770 (Rn)
Entrez Gene 80036 (Hs), 226025 (Mm), 309407 (Rn)
Human Protein Atlas ENSG00000083067 (Hs)
KEGG Gene hsa:80036 (Hs), mmu:226025 (Mm), rno:309407 (Rn)
OMIM 608961 (Hs)
Pharos Q9HCF6 (Hs)
RefSeq Nucleotide NM_020952 (Hs), NM_001035239 (Mm), NM_001191562 (Rn)
RefSeq Protein NP_066003 (Hs), NP_001030319 (Mm), NP_001178491 (Rn)
UniProtKB Q9HCF6 (Hs)
Wikipedia TRPM3 (Hs)
Associated Proteins Click here for help
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
calmodulin 17,29
Functional Characteristics Click here for help
TRPM31235: γ = 83 pS (Na+ current), 65 pS (Ca2+ current); conducts mono and di-valent cations non-selectively (PCa/PNa = 1.6) TRPM3α1: selective for monovalent cations (PCa/PCs~0.1);
TRPM3α2: conducts mono- and di-valent cations non-selectively (PCa/PCs = 1-10);
In- and outwardly rectifying currents by co-application of pregnenolone sulphate and clotrimazole or single application of CIM0216 [6,22]. Activated by clotrimazole but not by pregnenolone sulphate [5].
Ion Selectivity and Conductance Click here for help
Species:  Human
Rank order:  Cs+ = Ca2+ > Ca2+ [73.0 - 133.0 pS]
References:  3
Ion Selectivity and Conductance Comments
Listed conductance is for TRPM31325 variant. Selectivity and conductance is heavily dependent upon splice variant and conditions [3-4,17].
Voltage Dependence Click here for help
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -61.0 20.0 – 100.0 4 HEK 293 cells. Human
Inactivation  - -
Comments  TRPM31325 splice variant, activation by 10 μM D-erythrosphingosine, strong outward rectification.
Physical activators (Human)
heat (Q10 = 7.2 between 15 - 25°C), hypotonic cell swelling  [3,23-24]

Download all structure-activity data for this target as a CSV file go icon to follow link

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
NN-dimethyl-D-erythrosphingosine Small molecule or natural product Ligand is endogenous in the given species Hs Agonist - - 2x10-5 Physiological 4
⤷ Conc range: 2x10-5 M [4]
Holding voltage: Physiological
CIM0216 Small molecule or natural product Hs Activation 6.1 pEC50 - - 6,21
⤷ pEC50 6.1 [6,21]
sphingosine Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 4.9 pEC50 - Physiological 4
⤷ pEC50 4.9 (EC50 1.259x10-5 M) [4]
Holding voltage: Physiological
pregnenolone sulphate Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs - 4.9 pEC50 - - 25
⤷ pEC50 4.9 [25]
dihydrosphingosine Small molecule or natural product Ligand is endogenous in the given species Hs Agonist 4.7 pEC50 - - 4
⤷ pEC50 4.7 [4]
nifedipine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs - - - - -
⤷
epipregnanolone sulphate Small molecule or natural product Ligand is endogenous in the given species Hs - - - - - 12
⤷ [12]
pentafluoro-trityl clotrimazole analogue 29a Small molecule or natural product Hs Agonist - - - - 7
⤷ [7]
Activator Comments
TRPM3 has been shown to be constitutively open [3-4,11,17]. Also activated by hypotonic cell swelling [3]. Activation by store depletion was initially reported [11] but is disputed [3].
Gating inhibitors Click here for help
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
2-APB Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 4.0 pIC50 - - 28
⤷ pIC50 4.0 [28]
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Holding voltage (mV) Reference
isosakuranetin Small molecule or natural product Hs - 7.3 pIC50 - - 18
⤷ pIC50 7.3 (IC50 5x10-8 M) [18]
primidone Small molecule or natural product Approved drug Hs - 6.2 pIC50 - - 10
⤷ pIC50 6.2 [10]
maprotiline Small molecule or natural product Approved drug Click here for species-specific activity table Hs - 5.8 pIC50 - - 10
⤷ pIC50 5.8 [10]
diclofenac Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs - 5.2 pIC50 - - 20
⤷ pIC50 5.2 [20]
(S)-liquiritigenin Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs - 5.2 pIC50 - - 18
⤷ pIC50 5.2 [18]
naringenin Small molecule or natural product Click here for species-specific activity table Hs - 5.2 pIC50 - - 18-19
⤷ pIC50 5.2 [18-19]
Gd3+ Click here for species-specific activity table Hs Antagonist 4.0 pIC50 - - 3,11
⤷ pIC50 4.0 [3,11]
La3+ Click here for species-specific activity table Hs Antagonist 4.0 pIC50 - - 3,11
⤷ pIC50 4.0 [3,11]
chloroform Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 3.8 pIC50 - - 8
⤷ pIC50 3.8 (IC50 1.67x10-4 M) [8]
halothane Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 3.3 pIC50 - - 8
⤷ pIC50 3.3 (IC50 5.2x10-4 M) [8]
Mg2+ Click here for species-specific activity table Ligand is endogenous in the given species Mm Antagonist 2.0 pIC50 - - 17
⤷ pIC50 2.0 [17]
rosiglitazone Small molecule or natural product Approved drug Click here for species-specific activity table Hs - - - - - 13
⤷ [13]
extracellular Na+ Click here for species-specific activity table Ligand is endogenous in the given species Hs - - - - -
⤷ TRPM3α2 only
mefenamic acid Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs - - - - - 9
⤷ [9]
troglitazone Small molecule or natural product Approved drug Click here for species-specific activity table Hs - - - - -
⤷
pioglitazone Small molecule or natural product Approved drug Click here for species-specific activity table Hs - - - - - 13
⤷ independent of PPAR-γ [13]
View species-specific channel blocker tables
Channel Blocker Comments
Extracellular monovalent cations reduced (Na+>K+) outward currents through TRPM3α2 (short pore) but not through TRPM3α1 (long pore). Extracellular divalent cations reduced (Ca2+>Mg2+) outward currents through both TRPM3α1 and TRPM3α2 [17].
Tissue Distribution Click here for help
Kidney, brain, pulmonary endothelium, cultured trigeminal neurones, neuroblastoma cells, liver, pancreas, ovaries, testes, spinal cord, iris, retinal pigmented cells.
Species:  Human
Technique:  RT-PCR, Immunocytochemistry, Northern Blot, Western Blot.
References:  1-3,11,15,26-27
Brain (dentate gyrus, intermediate lateral septal nuclei, indusium giriseum, tenia tecta, epithelium of choroid plexus).
Species:  Mouse
Technique:  In situ hybridisation, Western Blot.
References:  17
Functional Assays Click here for help
Two-electrode voltage clamp, patch-clamp (whole-cell and single-channel recordings).
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Constitutively active current, responses to cell swelling, activation by ligands.
References:  3,11
Physiological Functions Click here for help
Probable role in osmosensation and renal Ca2+ homeostasis, mechanosensor, cation homeostasis in cerebrospinal fluid.
Species:  Human
Tissue:  Kidney, Brain.
References:  3,11
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Amyotrophic lateral sclerosis with frontotemporal dementia
Comments:  TRPM3 is a candidate gene for this disease.
References:  11,16
Disease:  Cataract 26, multiple types; CTRCT26
OMIM: 605749
Comments:  TRPM3 is a candidate gene for early-onset pulverulent cataract
References:  11,16
Disease:  Hemophagocytic lymphohistiocytosis
Synonyms: Hemophagocytic syndrome [Orphanet: ORPHA158032]
Disease Ontology: DOID:0050120
OMIM: 603552
Orphanet: ORPHA158032
Comments:  TRPM3 is a candidate gene for this disease.
References:  11,16
Disease:  Nephronophthisis 2; NPHP2
Synonyms: Nephronophthisis [Disease Ontology: DOID:12712]
Disease Ontology: DOID:12712
OMIM: 602088
Comments:  TRPM3 is a candidate gene for this disease.
References:  11,16

References

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1. Bollimuntha S, Ebadi M, Singh BB. (2006) TRPC1 protects human SH-SY5Y cells against salsolinol-induced cytotoxicity by inhibiting apoptosis. Brain Res, 1099 (1): 141-9. [PMID:16765919]

2. Fantozzi I, Zhang S, Platoshyn O, Remillard CV, Cowling RT, Yuan JX. (2003) Hypoxia increases AP-1 binding activity by enhancing capacitative Ca2+ entry in human pulmonary artery endothelial cells. Am J Physiol Lung Cell Mol Physiol, 285 (6): L1233-45. [PMID:12909593]

3. Grimm C, Kraft R, Sauerbruch S, Schultz G, Harteneck C. (2003) Molecular and functional characterization of the melastatin-related cation channel TRPM3. J Biol Chem, 278 (24): 21493-501. [PMID:12672799]

4. Grimm C, Kraft R, Schultz G, Harteneck C. (2005) Activation of the melastatin-related cation channel TRPM3 by D-erythro-sphingosine [corrected]. Mol Pharmacol, 67 (3): 798-805. [PMID:15550678]

5. Held K, Aloi VD, Freitas ACN, Janssens A, Segal A, Przibilla J, Philipp SE, Wang YT, Voets T, Vriens J. (2022) Pharmacological properties of TRPM3 isoforms are determined by the length of the pore loop. Br J Pharmacol, 179 (14): 3560-3575. [PMID:32780479]

6. Held K, Kichko T, De Clercq K, Klaassen H, Van Bree R, Vanherck JC, Marchand A, Reeh PW, Chaltin P, Voets T et al.. (2015) Activation of TRPM3 by a potent synthetic ligand reveals a role in peptide release. Proc Natl Acad Sci USA, 112 (11): E1363-72. [PMID:25733887]

7. Kahler JP, Aloi VD, Miedes Aliaga J, Kerselaers S, Voets T, Vriens J, Verhelst SHL, Barniol-Xicota M. (2023) Clotrimazole-Based Modulators of the TRPM3 Ion Channel Reveal Narrow Structure-Activity Relationship. ACS Chem Biol, 18 (3): 456-464. [PMID:36762958]

8. Kelemen B, Lisztes E, Vladár A, Hanyicska M, Almássy J, Oláh A, Szöllősi AG, Pénzes Z, Posta J, Voets T et al.. (2020) Volatile anaesthetics inhibit the thermosensitive nociceptor ion channel transient receptor potential melastatin 3 (TRPM3). Biochem Pharmacol, 174: 113826. [PMID:31987857]

9. Klose C, Straub I, Riehle M, Ranta F, Krautwurst D, Ullrich S, Meyerhof W, Harteneck C. (2011) Fenamates as TRP channel blockers: mefenamic acid selectively blocks TRPM3. Br J Pharmacol, 162 (8): 1757-69. [PMID:21198543]

10. Krügel U, Straub I, Beckmann H, Schaefer M. (2017) Primidone inhibits TRPM3 and attenuates thermal nociception in vivo. Pain, 158 (5): 856-867. [PMID:28106668]

11. Lee N, Chen J, Sun L, Wu S, Gray KR, Rich A, Huang M, Lin JH, Feder JN, Janovitz EB et al.. (2003) Expression and characterization of human transient receptor potential melastatin 3 (hTRPM3). J Biol Chem, 278 (23): 20890-7. [PMID:12672827]

12. Majeed Y, Agarwal AK, Naylor J, Seymour VA, Jiang S, Muraki K, Fishwick CW, Beech DJ. (2010) Cis-isomerism and other chemical requirements of steroidal agonists and partial agonists acting at TRPM3 channels. Br J Pharmacol, 161 (2): 430-41. [PMID:20735426]

13. Majeed Y, Bahnasi Y, Seymour VA, Wilson LA, Milligan CJ, Agarwal AK, Sukumar P, Naylor J, Beech DJ. (2011) Rapid and contrasting effects of rosiglitazone on transient receptor potential TRPM3 and TRPC5 channels. Mol Pharmacol, 79 (6): 1023-30. [PMID:21406603]

14. Nagase T, Kikuno R, Nakayama M, Hirosawa M, Ohara O. (2000) Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res, 7 (4): 273-81. [PMID:10997877]

15. Nealen ML, Gold MS, Thut PD, Caterina MJ. (2003) TRPM8 mRNA is expressed in a subset of cold-responsive trigeminal neurons from rat. J Neurophysiol, 90 (1): 515-20. [PMID:12634279]

16. Nilius B, Owsianik G, Voets T, Peters JA. (2007) Transient receptor potential cation channels in disease. Physiol Rev, 87 (1): 165-217. [PMID:17237345]

17. Oberwinkler J, Lis A, Giehl KM, Flockerzi V, Philipp SE. (2005) Alternative splicing switches the divalent cation selectivity of TRPM3 channels. J Biol Chem, 280 (23): 22540-8. [PMID:15824111]

18. Straub I, Krügel U, Mohr F, Teichert J, Rizun O, Konrad M, Oberwinkler J, Schaefer M. (2013) Flavanones that selectively inhibit TRPM3 attenuate thermal nociception in vivo. Mol Pharmacol, 84 (5): 736-50. [PMID:24006495]

19. Straub I, Mohr F, Stab J, Konrad M, Philipp SE, Oberwinkler J, Schaefer M. (2013) Citrus fruit and fabacea secondary metabolites potently and selectively block TRPM3. Br J Pharmacol, 168 (8): 1835-50. [PMID:23190005]

20. Suzuki H, Sasaki E, Nakagawa A, Muraki Y, Hatano N, Muraki K. (2016) Diclofenac, a nonsteroidal anti-inflammatory drug, is an antagonist of human TRPM3 isoforms. Pharmacol Res Perspect, 4 (3): e00232. [PMID:27433342]

21. Thiel G, Rubil S, Lesch A, Guethlein LA, Rössler OG. (2017) Transient receptor potential TRPM3 channels: Pharmacology, signaling, and biological functions. Pharmacol Res, 124: 92-99. [PMID:28720517]

22. Vriens J, Held K, Janssens A, Tóth BI, Kerselaers S, Nilius B, Vennekens R, Voets T. (2014) Opening of an alternative ion permeation pathway in a nociceptor TRP channel. Nat Chem Biol, 10 (3): 188-95. [PMID:24390427]

23. Vriens J, Owsianik G, Hofmann T, Philipp SE, Stab J, Chen X, Benoit M, Xue F, Janssens A, Kerselaers S et al.. (2011) TRPM3 is a nociceptor channel involved in the detection of noxious heat. Neuron, 70 (3): 482-94. [PMID:21555074]

24. Vriens J, Voets T. (2018) Sensing the heat with TRPM3. Pflugers Arch, 470 (5): 799-807. [PMID:29305649]

25. Wagner TF, Loch S, Lambert S, Straub I, Mannebach S, Mathar I, Düfer M, Lis A, Flockerzi V, Philipp SE et al.. (2008) Transient receptor potential M3 channels are ionotropic steroid receptors in pancreatic beta cells. Nat Cell Biol, 10 (12): 1421-30. [PMID:18978782]

26. Wistow G, Bernstein SL, Ray S, Wyatt MK, Behal A, Touchman JW, Bouffard G, Smith D, Peterson K. (2002) Expressed sequence tag analysis of adult human iris for the NEIBank Project: steroid-response factors and similarities with retinal pigment epithelium. Mol Vis, 8: 185-95. [PMID:12107412]

27. Wistow G, Bernstein SL, Wyatt MK, Fariss RN, Behal A, Touchman JW, Bouffard G, Smith D, Peterson K. (2002) Expressed sequence tag analysis of human RPE/choroid for the NEIBank Project: over 6000 non-redundant transcripts, novel genes and splice variants. Mol Vis, 8: 205-20. [PMID:12107410]

28. Xu SZ, Zeng F, Boulay G, Grimm C, Harteneck C, Beech DJ. (2005) Block of TRPC5 channels by 2-aminoethoxydiphenyl borate: a differential, extracellular and voltage-dependent effect. Br J Pharmacol, 145 (4): 405-14. [PMID:15806115]

29. Yap KL, Kim J, Truong K, Sherman M, Yuan T, Ikura M. (2000) Calmodulin target database. J Struct Funct Genomics, 1 (1): 8-14. [PMID:12836676]

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