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TRPM4

Family: Transient Receptor Potential channels

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Associated Proteins
Ion Selectivity and Conductance
Voltage Dependence
Activators
Gating Inhibitors
Pore Blockers
Tissue Distribution
Functional Assays
Physiological Functions
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Gene Expression and Pathophysiology
General Comments
References
Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 1208 19q13.32 TRPM4 transient receptor potential cation channel, subfamily M, member 4 11,16-17,28
Mouse 6 1 1213 7 B4 Trpm4 transient receptor potential cation channel, subfamily M, member 4 16
Rat 6 1 1208 1q22 Trpm4 transient receptor potential cation channel, subfamily M, member 4 6
Previous and Unofficial Names
Melastatin-like 2
MLS2s
Long TRPC4
Ca2+-activated non-selective cation channel 1
LTRPC4
FLJ20041
LTrpC-4
calcium-activated non-selective cation channel 1
long transient receptor potential channel 4
melastatin like 2 protein
transient receptor potential cation channel subfamily M member 4
transient receptor potential cation channel, subfamily M, member 4
TRPM4B
1110030C19Rik
AW047689
Database Links
Ensembl ENSG00000130529 (Hs), ENSMUSG00000038260 (Mm), ENSRNOG00000020714 (Rn)
Entrez Gene 54795 (Hs), 68667 (Mm), 171143 (Rn)
GeneCards TRPM4 (Hs)
GenitoUrinary Development Molecular Anatomy Project Trpm4 (Mm)
HomoloGene 23033 (Hs)
Human Protein Reference Database 09502 (Hs)
InterPro Q8TD43 (Hs), Q7TN37 (Mm), Q9ESQ5 (Rn)
KEGG Gene hsa:54795 (Hs), mmu:68667 (Mm), rno:171143 (Rn)
OMIM 606936 (Hs)
Orphanet Gene ORPHA209301 (Hs)
PharmGKB Gene PA38272 (Hs)
PhosphoSitePlus Q8TD43 (Hs), Q7TN37 (Mm)
Protein Ontology (PRO) PRO:000016700 (Hs)
RefSeq Nucleotide NM_017636 (Hs), NM_175130 (Mm), NM_001136229 (Rn)
RefSeq Protein NP_060106 (Hs), NP_780339 (Mm), NP_001129701 (Rn)
TreeFam ENSG00000130529 (Hs), ENSMUSG00000038260 (Mm), ENSRNOG00000020714 (Rn)
UniGene Hs. 467101 (Hs)
UniProt Q8TD43 (Hs), Q7TN37 (Mm), Q9ESQ5 (Rn)
Wikipedia TRPM4
Transient Receptor Potential channels
Search for 3D structures on the PDB
Search by keyword: Transient Receptor Potential channels TRPM4 Search by accession number: Q8TD43, Q9ESQ5, Q7TN37
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
SUR1 2,25
calmodulin 19
Ion Selectivity and Conductance
Species:  Human
Rank order:  Na+ > K+ > Cs+ > Li+ [25.0 pS]
References:  11,16-17
Ion Selectivity and Conductance Comments
Ca2+ impermeable.
Voltage Dependence
  V0.5 (mV)  τ (msec)  Reference  Cell type  Species 
Activation  -20.0 – 60.0 33.9 16,19,22,27 HEK 293 cells. Human
Inactivation  - 40.6 27
Voltage Dependence Comments
Range of voltage activation depends on intracellular Ca2+ concentration, PIP2, PKC phosphorylation, presence of calmodulin [14,16,19,21-22].
Other channel blockers
intracellular nucleotides including ATP, ADP, AMP and AMP-PNP with an IC50 range of 1.3-1.9 μM
Physical activators (Human)
membrane depolarization (V½ = -20 mV to + 60 mV dependent upon conditions) in the presence of elevated [Ca2+]i, heat (Q10 = 8.5 @ +25 mV between 15 and 25°C)
Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
BTP2 Hs 8.1 pEC50 - -80.0 26
decavanadate Hs 5.7 pEC50 - -100.0 18
Cai2+ Hs 3.9 – 6.5 (median: 5.4) pEC50 - -100.0 – 100.0 12,14,16,18-19,26
PIP2 Hs 5.3 pEC50 - 100.0 14
PIP2 Mm 5.2 pEC50 - -80.0 29
View species-specific activator tables
Activator Comments
Ca2+ affinity is regulated by PIP2, phosphorylation by PKC. Decreased Ca2+ affinity during desensitisation, strong desensitisation in inside-out patches [14,16,19,21-22]. U73122 prevents TRPM4 desensitisation and rescues activity [14]. Potentiation by BTP2 is increased at positive holding potentials [26].
Gating inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
clotrimazole Hs - - 1x10-6 - 1x10-5 100.0 23
ADP Hs 5.7 pIC50 - 100.0 20
flufenamic acid Mm 5.6 pIC50 - 100.0 27
ATP Hs 4.9 pIC50 - 100.0 20
AMP Hs 4.7 pIC50 - 100.0 20
AMP-PNP Hs 4.7 pIC50 - 100.0 20
View species-specific gating inhibitor tables
Pore Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
ATP Mm 6.1 pIC50 - 100.0 27
ATP Hs 5.8 pIC50 - 100.0 20
spermine Mm 4.5 pIC50 - 100.0 27
spermine Hs 4.2 pIC50 - 100.0 20
View species-specific pore blocker tables
Pore Blocker Comments
Pore mutation Asp984 -> Ala results in a non-functional channel with a dominant negative phenotype; block by spermine is reduced by pore mutation Glu981 -> Ala [17].

Explore drug-target interactions for this set of compounds using iPHACE

Tissue Distribution
Small intestine, prostate, colon, kidneys (proximal convoluted tubule, distal convoluted tubule, proximal straight tubule, loop of Henle, cortical collecting duct), testes, heart, lymphocytes, spleen, lung, brain, pituitary, skeletal muscle, stomach, adipose tissue, bone.
Species:  Human
Technique:  Northern Blot, Western Blot, RT-PCR, TaqMan
References:  1,5,11-12,16,28
Thymocytes, intestine, aortic endothelium, placenta, pancreas.
Species:  Mouse
Technique:  Western Blot, Northern Blot
References:  11,16
Cerebral arteries, smooth muscle cells.
Species:  Rat
Technique:  RT-PCR
References:  4
Functional Assays
Patch clamp (whole-cell and single-channel recordings).
Species:  Human
Tissue:  Overexpression in HEK 293 cells.
Response measured:  Current activation, negative feedback on Ca2+ entry, depolarisation of cell membrane potential.
References:  12,14,16-19,26
Patch clamp (whole-cell and single-channel recordings).
Species:  Human
Tissue:  Jurkat cells.
Response measured:  PHA-induced interleukin-2 release, oscillation of intracellular Ca2+ concentration, cell membrane potential.
References:  11
Whole-cell patch clamp, Ca2+ analysis, down-regulation of TRPM4 by expression of short splice variant TRPM4a.
Species:  Rat
Tissue:  β-cell model insulinoma INS-1 cells.
Response measured:  Glucose-induced insulin secretion, voltage clamp analysis.
References:  3
Whole-cell patch clamp, arteriography.
Species:  Rat
Tissue:  Smooth muscle cells, cerebral arteries.
Response measured:  Single-channel current, membrane potential, vessel diameter and tension.
References:  4
Patch clamp (whole-cell and single-channel recordings).
Species:  Mouse
Tissue:  Overexpression in HEK 293 cells.
Response measured:  Current activation, negative feedback on Ca2+ entry, depolarisation of cell membrane potential.
References:  16,27
Physiological Functions
Candidate for endogenous calcium-activated cation (CAN) channels, negative feedback regulator of Ca2+ entry, involved in oscillatory electrical activity and the generation of the Bayliss effect in smooth muscle.
Species:  Human
Tissue:  Widely expressed.
References:  9,12,16,22
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Trpm4tm1.1Mfre Trpm4tm1.1Mfre/Trpm4tm1.1Mfre
involves: 129S1/Sv * 129X1/SvJ * BALB/cJ		 MGI:1915917  MP:0004231 abnormal calcium ion homeostasis PMID: 17293867 
Trpm4tm1.1Knt Trpm4tm1.1Knt/Trpm4tm1.1Knt
Not Specified		 MGI:1915917  MP:0002376 abnormal dendritic cell physiology PMID: 18758465 
Trpm4tm1.1Knt|Trpm5tm1Csz Trpm4tm1.1Knt/Trpm4tm1.1Knt,Trpm5tm1Csz/Trpm5tm1Csz
involves: 129S1/Sv * 129X1/SvJ		 MGI:1861718  MGI:1915917  MP:0002376 abnormal dendritic cell physiology PMID: 18758465 
Trpm4tm1.1Knt Trpm4tm1.1Knt/Trpm4tm1.1Knt
Not Specified		 MGI:1915917  MP:0008127 decreased dendritic cell number PMID: 18758465 
Trpm4tm1.1Knt|Trpm5tm1Csz Trpm4tm1.1Knt/Trpm4tm1.1Knt,Trpm5tm1Csz/Trpm5tm1Csz
involves: 129S1/Sv * 129X1/SvJ		 MGI:1861718  MGI:1915917  MP:0008127 decreased dendritic cell number PMID: 18758465 
Trpm4tm1.1Mfre Trpm4tm1.1Mfre/Trpm4tm1.1Mfre
involves: 129S1/Sv * 129X1/SvJ * BALB/cJ		 MGI:1915917  MP:0005596 increased susceptibility to type I hypersensitivity reaction PMID: 17293867 
Trpm4tm1.1Mfre Trpm4tm1.1Mfre/Trpm4tm1.1Mfre
involves: 129S1/Sv * 129X1/SvJ * BALB/cJ		 MGI:1915917  MP:0003070 increased vascular permeability PMID: 17293867 
Clinically-Relevant Mutations and Pathophysiology
Role:  Hyper-responsiveness in immune cells, induction of pro-inflammatory conditions, allergy, defective surfactant secretion in pneumocytes, defective Bayliss effect, trigger for paroxysmal depolarisation shift, spreading depression-like hypoxic depolarisation, stroke, cardiac hypertrophy and arrythmia.
References:  7-8,11,15,24-25
Mutations not determined
Disease:  Progressive familial heart block, type IB, PFHB1B
OMIM:  604559
Orphanet:  871
References: 
Mutations not determined
Gene Expression and Pathophysiology
Overexpression.
Tissue or cell type:  Skeletal and cardiac muscle.
Pathophysiology:  Muscular dystrophy and cardiomyopathy.
Species:  None
Technique: 
References:  10
General Comments
Human: long splice-variant TRPM4b (1214 AA), short splice-variant TRPM4a (1040 AA, lacks first 174 AA), shortest splice variant TRPM4c (537 AA, lacks N-terminal) [16].

Mouse: two short splice variants from brain [13].

REFERENCES

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1. Chabardes-Garonne, D; Mejean, A; Aude, JC; Cheval, L; Di Stefano, A; Gaillard, MC; Imbert-Teboul, M; Wittner, M; Balian, C; Anthouard, V; Robert, C; Segurens, B; Wincker, P; Weissenbach, J; Doucet, A; Elalouf, JM. (2003) A panoramic view of gene expression in the human kidney. Proc. Natl. Acad. Sci. U.S.A., 100 (23): 13710-5. [PMID:14595018]

2. Chen, M; Dong, Y; Simard, JM. (2003) Functional coupling between sulfonylurea receptor type 1 and a nonselective cation channel in reactive astrocytes from adult rat brain. J. Neurosci., 23 (24): 8568-77. [PMID:13679426]

3. Cheng, H; Beck, A; Launay, P; Gross, SA; Stokes, AJ; Kinet, JP; Fleig, A; Penner, R. (2007) TRPM4 controls insulin secretion in pancreatic beta-cells. Cell Calcium, 41 (1): 51-61. [PMID:16806463]

4. Earley, S; Waldron, BJ; Brayden, JE. (2004) Critical role for transient receptor potential channel TRPM4 in myogenic constriction of cerebral arteries. Circ. Res., 95 (9): 922-9. [PMID:15472118]

5. Fonfria, E; Murdock, PR; Cusdin, FS; Benham, CD; Kelsell, RE; McNulty, S. (2006) Tissue distribution profiles of the human TRPM cation channel family. J. Recept. Signal Transduct. Res., 26 (3): 159-78. [PMID:16777713]

6. Gibbs, RA; Weinstock, GM; Metzker, ML; Muzny, DM; Sodergren, EJ; Scherer, S; Scott, G; Steffen, D; Worley, KC; Burch, PE; Okwuonu, G; Hines, S; Lewis, L; DeRamo, C; Delgado, O; Dugan-Rocha, S; Miner, G; Morgan, M; Hawes, A; Gill, R; Celera, RA; Adams, MD; Amanatides, PG; Baden-Tillson, H; Barnstead, M; Chin, S; Evans, CA; Ferriera, S; Fosler, C; Glodek, A; Gu, Z; Jennings, D; Kraft, CL; Nguyen, T; Pfannkoch, CM; Sitter, C; Sutton, GG; Venter, JC; Woodage, T; Smith, D; Lee, HM; Gustafson, E; Cahill, P; Kana, A; Doucette-Stamm, L; Weinstock, K; Fechtel, K; Weiss, RB; Dunn, DM; Green, ED; Blakesley, RW; Bouffard, GG; De Jong, PJ; Osoegawa, K; Zhu, B; Marra, M; Schein, J; Bosdet, I; Fjell, C; Jones, S; Krzywinski, M; Mathewson, C; Siddiqui, A; Wye, N; McPherson, J; Zhao, S; Fraser, CM; Shetty, J; Shatsman, S; Geer, K; Chen, Y; Abramzon, S; Nierman, WC; Havlak, PH; Chen, R; Durbin, KJ; Egan, A; Ren, Y; Song, XZ; Li, B; Liu, Y; Qin, X; Cawley, S; Worley, KC; Cooney, AJ; D'Souza, LM; Martin, K; Wu, JQ; Gonzalez-Garay, ML; Jackson, AR; Kalafus, KJ; McLeod, MP; Milosavljevic, A; Virk, D; Volkov, A; Wheeler, DA; Zhang, Z; Bailey, JA; Eichler, EE; Tuzun, E; Birney, E; Mongin, E; Ureta-Vidal, A; Woodwark, C; Zdobnov, E; Bork, P; Suyama, M; Torrents, D; Alexandersson, M; Trask, BJ; Young, JM; Huang, H; Wang, H; Xing, H; Daniels, S; Gietzen, D; Schmidt, J; Stevens, K; Vitt, U; Wingrove, J; Camara, F; Mar Albà, M; Abril, JF; Guigo, R; Smit, A; Dubchak, I; Rubin, EM; Couronne, O; Poliakov, A; Hübner, N; Ganten, D; Goesele, C; Hummel, O; Kreitler, T; Lee, YA; Monti, J; Schulz, H; Zimdahl, H; Himmelbauer, H; Lehrach, H; Jacob, HJ; Bromberg, S; Gullings-Handley, J; Jensen-Seaman, MI; Kwitek, AE; Lazar, J; Pasko, D; Tonellato, PJ; Twigger, S; Ponting, CP; Duarte, JM; Rice, S; Goodstadt, L; Beatson, SA; Emes, RD; Winter, EE; Webber, C; Brandt, P; Nyakatura, G; Adetobi, M; Chiaromonte, F; Elnitski, L; Eswara, P; Hardison, RC; Hou, M; Kolbe, D; Makova, K; Miller, W; Nekrutenko, A; Riemer, C; Schwartz, S; Taylor, J; Yang, S; Zhang, Y; Lindpaintner, K; Andrews, TD; Caccamo, M; Clamp, M; Clarke, L; Curwen, V; Durbin, R; Eyras, E; Searle, SM; Cooper, GM; Batzoglou, S; Brudno, M; Sidow, A; Stone, EA; Venter, JC; Payseur, BA; Bourque, G; López-Otín, C; Puente, XS; Chakrabarti, K; Chatterji, S; Dewey, C; Pachter, L; Bray, N; Yap, VB; Caspi, A; Tesler, G; Pevzner, PA; Haussler, D; Roskin, KM; Baertsch, R; Clawson, H; Furey, TS; Hinrichs, AS; Karolchik, D; Kent, WJ; Rosenbloom, KR; Trumbower, H; Weirauch, M; Cooper, DN; Stenson, PD; Ma, B; Brent, M; Arumugam, M; Shteynberg, D; Copley, RR; Taylor, MS; Riethman, H; Mudunuri, U; Peterson, J; Guyer, M; Felsenfeld, A; Old, S; Mockrin, S; Collins, F. (2004) Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature, 428 (6982): 493-521. [PMID:15057822]

7. Guinamard, R; Chatelier, A; Demion, M; Potreau, D; Patri, S; Rahmati, M; Bois, P. (2004) Functional characterization of a Ca(2+)-activated non-selective cation channel in human atrial cardiomyocytes. J. Physiol. (Lond.), 558 (Pt 1): 75-83. [PMID:15121803]

8. Guinamard, R; Chatelier, A; Lenfant, J; Bois, P. (2004) Activation of the Ca(2+)-activated nonselective cation channel by diacylglycerol analogues in rat cardiomyocytes. J. Cardiovasc. Electrophysiol., 15 (3): 342-8. [PMID:15030426]

9. Hofmann, T; Chubanov, V; Gudermann, T; Montell, C. (2003) TRPM5 is a voltage-modulated and Ca(2+)-activated monovalent selective cation channel. Curr. Biol., 13 (13): 1153-8. [PMID:12842017]

10. Iwata, Y; Katanosaka, Y; Arai, Y; Komamura, K; Miyatake, K; Shigekawa, M. (2003) A novel mechanism of myocyte degeneration involving the Ca2+-permeable growth factor-regulated channel. J. Cell Biol., 161 (5): 957-67. [PMID:12796481]

11. Launay, P; Cheng, H; Srivatsan, S; Penner, R; Fleig, A; Kinet, JP. (2004) TRPM4 regulates calcium oscillations after T cell activation. Science, 306 (5700): 1374-7. [PMID:15550671]

12. Launay, P; Fleig, A; Perraud, AL; Scharenberg, AM; Penner, R; Kinet, JP. (2002) TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization. Cell, 109 (3): 397-407. [PMID:12015988]

13. Murakami, M; Xu, F; Miyoshi, I; Sato, E; Ono, K; Iijima, T. (2003) Identification and characterization of the murine TRPM4 channel. Biochem. Biophys. Res. Commun., 307 (3): 522-8. [PMID:12893253]

14. Nilius, B; Mahieu, F; Prenen, J; Janssens, A; Owsianik, G; Vennekens, R; Voets, T. (2006) The Ca2+-activated cation channel TRPM4 is regulated by phosphatidylinositol 4,5-biphosphate. EMBO J., 25 (3): 467-78. [PMID:16424899]

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

16. Nilius, B; Prenen, J; Droogmans, G; Voets, T; Vennekens, R; Freichel, M; Wissenbach, U; Flockerzi, V. (2003) Voltage dependence of the Ca2+-activated cation channel TRPM4. J. Biol. Chem., 278 (33): 30813-20. [PMID:12799367]

17. Nilius, B; Prenen, J; Janssens, A; Owsianik, G; Wang, C; Zhu, MX; Voets, T. (2005) The selectivity filter of the cation channel TRPM4. J. Biol. Chem., 280 (24): 22899-906. [PMID:15845551]

18. Nilius, B; Prenen, J; Janssens, A; Voets, T; Droogmans, G. (2004) Decavanadate modulates gating of TRPM4 cation channels. J. Physiol. (Lond.), 560 (Pt 3): 753-65. [PMID:15331675]

19. Nilius, B; Prenen, J; Tang, J; Wang, C; Owsianik, G; Janssens, A; Voets, T; Zhu, MX. (2005) Regulation of the Ca2+ sensitivity of the nonselective cation channel TRPM4. J. Biol. Chem., 280 (8): 6423-33. [PMID:15590641]

20. Nilius, B; Prenen, J; Voets, T; Droogmans, G. (2004) Intracellular nucleotides and polyamines inhibit the Ca2+-activated cation channel TRPM4b. Pflugers Arch., 448 (1): 70-5. [PMID:14758478]

21. Nilius, B; Talavera, K; Owsianik, G; Prenen, J; Droogmans, G; Voets, T. (2005) Gating of TRP channels: a voltage connection?. J. Physiol. (Lond.), 567 (Pt 1): 35-44. [PMID:15878939]

22. Nilius, B; Vennekens, R. (2006) From cardiac cation channels to the molecular dissection of the transient receptor potential channel TRPM4. Pflugers Arch., 453 (3): 313-21. [PMID:16680483]

23. Nina D. Ullrich. (2005) PhD Thesis. in TRPM4 and TRPM5: Functional characterisation and comparison of two novel Ca2+-activated cation channels of the TRPM subfamily Faculteit Geneeskunde, Dept. Moleculaire Celbiologie, KU Leuven.

24. Schiller, Y. (2004) Activation of a calcium-activated cation current during epileptiform discharges and its possible role in sustaining seizure-like events in neocortical slices. J. Neurophysiol., 92 (2): 862-72. [PMID:15277598]

25. Simard, JM; Chen, M; Tarasov, KV; Bhatta, S; Ivanova, S; Melnitchenko, L; Tsymbalyuk, N; West, GA; Gerzanich, V. (2006) Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke. Nat. Med., 12 (4): 433-40. [PMID:16550187]

26. Takezawa, R; Cheng, H; Beck, A; Ishikawa, J; Launay, P; Kubota, H; Kinet, JP; Fleig, A; Yamada, T; Penner, R. (2006) A pyrazole derivative potently inhibits lymphocyte Ca2+ influx and cytokine production by facilitating transient receptor potential melastatin 4 channel activity. Mol. Pharmacol., 69 (4): 1413-20. [PMID:16407466]

27. Ullrich, ND; Voets, T; Prenen, J; Vennekens, R; Talavera, K; Droogmans, G; Nilius, B. (2005) Comparison of functional properties of the Ca2+-activated cation channels TRPM4 and TRPM5 from mice. Cell Calcium, 37 (3): 267-78. [PMID:15670874]

28. Xu, XZ; Moebius, F; Gill, DL; Montell, C. (2001) Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform. Proc. Natl. Acad. Sci. U.S.A., 98 (19): 10692-7. [PMID:11535825]

29. Zhang, Z; Okawa, H; Wang, Y; Liman, ER. (2005) Phosphatidylinositol 4,5-bisphosphate rescues TRPM4 channels from desensitization. J. Biol. Chem., 280 (47): 39185-92. [PMID:16186107]

To cite this database page, please use the following:

David E. Clapham, Bernd Nilius, Grzegorz Owsianik.
Transient Receptor Potential channels: TRPM4. Last modified on 20/01/2012. Accessed on 18/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=496.


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