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TRPC4

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Target not currently curated in GtoImmuPdb

Target id: 489

Nomenclature: TRPC4

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 6 1 977 13q13.3 TRPC4 transient receptor potential cation channel subfamily C member 4
Mouse 6 1 974 3 25.43 cM Trpc4 transient receptor potential cation channel, subfamily C, member 4
Rat 6 1 977 2q26 Trpc4 transient receptor potential cation channel, subfamily C, member 4
Previous and Unofficial Names Click here for help
CCE1 | TRP4 | capacitative calcium entry channel 1 | short transient receptor potential channel 4 | transient receptor potential 4 | STRPC4 | transient receptor potential cation channel
Database Links Click here for help
Alphafold Q9UBN4 (Hs), Q9QUQ5 (Mm), O35119 (Rn)
CATH/Gene3D 1.25.40.20
ChEMBL Target CHEMBL4295971 (Hs), CHEMBL1741219 (Mm)
Ensembl Gene ENSG00000133107 (Hs), ENSMUSG00000027748 (Mm), ENSRNOG00000011133 (Rn)
Entrez Gene 7223 (Hs), 22066 (Mm), 84494 (Rn)
Human Protein Atlas ENSG00000133107 (Hs)
KEGG Gene hsa:7223 (Hs), mmu:22066 (Mm), rno:84494 (Rn)
OMIM 603651 (Hs)
Pharos Q9UBN4 (Hs)
RefSeq Nucleotide NM_016179 (Hs), NM_016984 (Mm), NM_001083115 (Rn), NM_080396 (Rn)
RefSeq Protein NP_057263 (Hs), NP_058680 (Mm), NP_536321 (Rn), NP_001076584 (Rn)
UniProtKB Q9UBN4 (Hs), Q9QUQ5 (Mm), O35119 (Rn)
Wikipedia TRPC4 (Hs)
Associated Proteins Click here for help
Heteromeric Pore-forming Subunits
Name References
TRPC1 28
TRPC3 29
TRPC5 28
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
calmodulin 30
NHERF 31
MxA 11
IP3R3 30
caveolin-1 15
D2 receptor 6
Gαi2 8
STIM1 7
ZO-1 26
SESTD1 13
αII-spectrin 16
Functional Characteristics Click here for help
γ = 30 –41 pS, conducts mono and di-valent cations non-selectively (PCa/PNa = 1.1 – 7.7); dual (inward and outward) rectification
Ion Selectivity and Conductance Click here for help
Species:  Mouse
Rank order:  Ca2+ = Na+
References:  23,28
Chemical activators (Human)
NO-mediated cysteine S-nitrosylation, potentiation by extracellular protons

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
(-)-englerin A Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Agonist 7.9 pEC50 - - 1
⤷ pEC50 7.9 [1]
tonantzitlolone Small molecule or natural product Click here for species-specific activity table Hs Activation 6.9 pEC50 - - 22
⤷ pEC50 6.9 (EC50 1.23x10-7 M) [22]
La3+ Click here for species-specific activity table Hs - - - - -
⤷ μM range
Activator Comments
TRPC4 has also been reported to be activated by receptors coupled to Gαi proteins [8], and potentiated by extracellular protons [24]. Intracellular calcium potentiates TRPC4β [2].
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
niflumic acid Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Mm Antagonist - - 3x10-5 -60.0 33
⤷ Conc range: 3x10-5 M [33]
Holding voltage: -60.0 mV
M084 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Inhibition 5.0 pKi - - 25
⤷ pKi 5.0 (Ki 1.03x10-5 M) [25]
Description: As determined by the FMP assay using DAMGO to stimulate Gi/o via the coexpressed μ receptor.
Pico145 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.5 pIC50 - - 21
⤷ pIC50 9.5 (IC50 3.5x10-10 M) [21]
Description: Inhibition of englerin A-induced calcium entry in to HEK293 cells stably expressing hTRPC4 by calcium imaging.
HC-070 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 7.3 pIC50 - - 9
⤷ pIC50 7.3 (IC50 4.6x10-8 M) [9]
Description: Inhibition of calcium entry via recombinantly-expressed hTRPC4 in cellular assays.
ML204 Small molecule or natural product Mm Inhibition 5.5 pIC50 - - 14
⤷ pIC50 5.5 (IC50 2.91x10-6 M) [14]
M084 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.3 pIC50 - - 35
⤷ pIC50 5.3 (IC50 5.43x10-6 M) [35]
clemizole Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs - 5.2 pIC50 - - 20
⤷ pIC50 5.2 (IC50 6.4x10-6 M) [20]
2-APB Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs - - - - -
⤷
La3+ Click here for species-specific activity table Hs - - - - -
⤷ mM range
SKF96365 Small molecule or natural product Click here for species-specific activity table Hs - - - - -
⤷
View species-specific channel blocker tables
Channel Blocker Comments
It is not clear whether any of these blockers are pore blockers or gating inhibitors. PIP2 has been reported to inhibit TRPC4α [17].
Tissue Distribution Click here for help
Heart, brain, pancreas, placenta, kidney.
Species:  Human
Technique:  Northern Blot
References:  12
Arterial endothelial cells and smooth muscle cells
Species:  Human
Technique:  Immunohistochemistry
References:  34
Brain: olfactory bulb, hippocampus, cortex, septum and cerebellum.
Species:  Mouse
Technique:  Immunohistochemistry
References:  3-4
Inner granule cell layer of olfactory bulb.
Species:  Rat
Technique:  In situ hybridisation
References:  19
Hippocampal CA1 & CA3 areas, dentate gyrus.
Species:  Rat
Technique:  Immunohistochemistry
References:  10
Functional Assays Click here for help
Nonselective cation current activated by Gq stimulation.
Species:  Mouse
Tissue:  Heterologous expression.
Response measured:  Cation current.
References:  23,28
Physiological Functions Click here for help
Mediates agonist dependent vasorelaxation in the vascular endothelium.
Species:  Mouse
Tissue:  Vascular endothelium.
References:  5
Proposed as a component of muscarinic receptor-activated nonselective current in smooth muscle cells.
Species:  Mouse
Tissue:  Visceral smooth muscle.
References:  10
Heteromer of TRPC1/C4 contributes to seizure activity in lateral septal neurons.
Species:  Mouse
Tissue:  Brain: septum
References:  18
Heteromer of TRPC1/C4 contributes to synaptic responses in olfactory bulb neurons.
Species:  Mouse
Tissue:  Brain: olfactory bulb.
References:  27
Contributes to muscarinic activated current in gastric smooth muscle cells.
Species:  Mouse
Tissue:  Gastrointestinal smooth muscle cells.
References:  32
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Trpc4tm1Bni Trpc4tm1Bni/Trpc4tm1Bni
either: (involves: 129S1/Sv * 129X1/SvJ) or (involves: 129S1/Sv * 129X1/SvJ * C57BL/6J)		 MGI:109525  MP:0005591 decreased vasodilation PMID: 11175743 
Biologically Significant Variants Click here for help
Type:  Splice variant
Species:  Rat
Description:  β-isoform
Amino acids:  893
Nucleotide accession:  NM_001083115
Protein accession:  NP_001076584
Type:  Splice variant
Species:  Rat
Description:  α-isoform
Amino acids:  977
Nucleotide accession:  NM_080396
Protein accession:  NP_536321
General Comments
Activated by stimulation of GPCRs coupled to Gq stimulation. Precise pathway is unclear. Also, potentiated by 10-100 μM La3+ and Gd3+. When complexed with TRPC1, a current with a unique I-V relationship is formed [28].

References

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1. Akbulut Y, Gaunt HJ, Muraki K, Ludlow MJ, Amer MS, Bruns A, Vasudev NS, Radtke L, Willot M, Hahn S et al.. (2015) (-)-Englerin A is a potent and selective activator of TRPC4 and TRPC5 calcium channels. Angew Chem Int Ed Engl, 54 (12): 3787-91. [PMID:25707820]

2. Blair NT, Kaczmarek JS, Clapham DE. (2009) Intracellular calcium strongly potentiates agonist-activated TRPC5 channels. J Gen Physiol, 133 (5): 525-46. [PMID:19398778]

3. Boisseau S, Kunert-Keil C, Lucke S, Bouron A. (2009) Heterogeneous distribution of TRPC proteins in the embryonic cortex. Histochem Cell Biol, 131 (3): 355-63. [PMID:18989690]

4. Chung YH, Sun Ahn H, Kim D, Hoon Shin D, Su Kim S, Yong Kim K, Bok Lee W, Ik Cha C. (2006) Immunohistochemical study on the distribution of TRPC channels in the rat hippocampus. Brain Res, 1085 (1): 132-7. [PMID:16580647]

5. Freichel M, Suh SH, Pfeifer A, Schweig U, Trost C, Weissgerber P, Biel M, Philipp S, Freise D, Droogmans G et al.. (2001) Lack of an endothelial store-operated Ca2+ current impairs agonist-dependent vasorelaxation in TRP4-/- mice. Nat Cell Biol, 3 (2): 121-7. [PMID:11175743]

6. Hannan MA, Kabbani N, Paspalas CD, Levenson R. (2008) Interaction with dopamine D2 receptor enhances expression of transient receptor potential channel 1 at the cell surface. Biochim Biophys Acta, 1778 (4): 974-82. [PMID:18261457]

7. Huang GN, Zeng W, Kim JY, Yuan JP, Han L, Muallem S, Worley PF. (2006) STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels. Nat Cell Biol, 8 (9): 1003-10. [PMID:16906149]

8. Jeon JP, Hong C, Park EJ, Jeon JH, Cho NH, Kim IG, Choe H, Muallem S, Kim HJ, So I. (2012) Selective Gαi subunits as novel direct activators of transient receptor potential canonical (TRPC)4 and TRPC5 channels. J Biol Chem, 287 (21): 17029-39. [PMID:22457348]

9. Just S, Chenard BL, Ceci A, Strassmaier T, Chong JA, Blair NT, Gallaschun RJ, Del Camino D, Cantin S, D'Amours M et al.. (2018) Treatment with HC-070, a potent inhibitor of TRPC4 and TRPC5, leads to anxiolytic and antidepressant effects in mice. PLoS ONE, 13 (1): e0191225. [PMID:29385160]

10. Lee KP, Jun JY, Chang IY, Suh SH, So I, Kim KW. (2005) TRPC4 is an essential component of the nonselective cation channel activated by muscarinic stimulation in mouse visceral smooth muscle cells. Mol Cells, 20 (3): 435-41. [PMID:16404161]

11. Lussier MP, Cayouette S, Lepage PK, Bernier CL, Francoeur N, St-Hilaire M, Pinard M, Boulay G. (2005) MxA, a member of the dynamin superfamily, interacts with the ankyrin-like repeat domain of TRPC. J Biol Chem, 280 (19): 19393-400. [PMID:15757897]

12. McKay RR, Szymeczek-Seay CL, Lievremont JP, Bird GS, Zitt C, Jüngling E, Lückhoff A, Putney Jr JW. (2000) Cloning and expression of the human transient receptor potential 4 (TRP4) gene: localization and functional expression of human TRP4 and TRP3. Biochem J, 351 Pt 3: 735-46. [PMID:11042129]

13. Miehe S, Bieberstein A, Arnould I, Ihdene O, Rütten H, Strübing C. (2010) The phospholipid-binding protein SESTD1 is a novel regulator of the transient receptor potential channels TRPC4 and TRPC5. J Biol Chem, 285 (16): 12426-34. [PMID:20164195]

14. Miller M, Shi J, Zhu Y, Kustov M, Tian JB, Stevens A, Wu M, Xu J, Long S, Yang P et al.. (2011) Identification of ML204, a novel potent antagonist that selectively modulates native TRPC4/C5 ion channels. J Biol Chem, 286 (38): 33436-46. [PMID:21795696]

15. Murata T, Lin MI, Stan RV, Bauer PM, Yu J, Sessa WC. (2007) Genetic evidence supporting caveolae microdomain regulation of calcium entry in endothelial cells. J Biol Chem, 282 (22): 16631-43. [PMID:17416589]

16. Odell AF, Van Helden DF, Scott JL. (2008) The spectrin cytoskeleton influences the surface expression and activation of human transient receptor potential channel 4 channels. J Biol Chem, 283 (7): 4395-407. [PMID:18048348]

17. Otsuguro K, Tang J, Tang Y, Xiao R, Freichel M, Tsvilovskyy V, Ito S, Flockerzi V, Zhu MX, Zholos AV. (2008) Isoform-specific inhibition of TRPC4 channel by phosphatidylinositol 4,5-bisphosphate. J Biol Chem, 283 (15): 10026-36. [PMID:18230622]

18. Phelan KD, Shwe UT, Abramowitz J, Wu H, Rhee SW, Howell MD, Gottschall PE, Freichel M, Flockerzi V, Birnbaumer L et al.. (2013) Canonical transient receptor channel 5 (TRPC5) and TRPC1/4 contribute to seizure and excitotoxicity by distinct cellular mechanisms. Mol Pharmacol, 83 (2): 429-38. [PMID:23188715]

19. Philipp S, Hambrecht J, Braslavski L, Schroth G, Freichel M, Murakami M, Cavalié A, Flockerzi V. (1998) A novel capacitative calcium entry channel expressed in excitable cells. EMBO J, 17 (15): 4274-82. [PMID:9687496]

20. Richter JM, Schaefer M, Hill K. (2014) Clemizole hydrochloride is a novel and potent inhibitor of transient receptor potential channel TRPC5. Mol Pharmacol, 86 (5): 514-21. [PMID:25140002]

21. Rubaiy HN, Ludlow MJ, Henrot M, Gaunt HJ, Miteva K, Cheung SY, Tanahashi Y, Hamzah N, Musialowski KE, Blythe NM et al.. (2017) Picomolar, selective, and subtype-specific small-molecule inhibition of TRPC1/4/5 channels. J Biol Chem, 292 (20): 8158-8173. [PMID:28325835]

22. Rubaiy HN, Ludlow MJ, Siems K, Norman K, Foster R, Wolf D, Beutler JA, Beech DJ. (2018) Tonantzitlolone is a nanomolar potency activator of transient receptor potential canonical 1/4/5 channels. Br J Pharmacol, 175 (16): 3361-3368. [PMID:29859013]

23. Schaefer M, Plant TD, Obukhov AG, Hofmann T, Gudermann T, Schultz G. (2000) Receptor-mediated regulation of the nonselective cation channels TRPC4 and TRPC5. J Biol Chem, 275 (23): 17517-26. [PMID:10837492]

24. Semtner M, Schaefer M, Pinkenburg O, Plant TD. (2007) Potentiation of TRPC5 by protons. J Biol Chem, 282 (46): 33868-78. [PMID:17884814]

25. Sharma S, Hopkins CR. (2019) Review of Transient Receptor Potential Canonical (TRPC5) Channel Modulators and Diseases. J Med Chem, 62 (17): 7589-7602. [PMID:30943030]

26. Song X, Zhao Y, Narcisse L, Duffy H, Kress Y, Lee S, Brosnan CF. (2005) Canonical transient receptor potential channel 4 (TRPC4) co-localizes with the scaffolding protein ZO-1 in human fetal astrocytes in culture. Glia, 49 (3): 418-29. [PMID:15540229]

27. Stroh O, Freichel M, Kretz O, Birnbaumer L, Hartmann J, Egger V. (2012) NMDA receptor-dependent synaptic activation of TRPC channels in olfactory bulb granule cells. J Neurosci, 32 (17): 5737-46. [PMID:22539836]

28. Strübing C, Krapivinsky G, Krapivinsky L, Clapham DE. (2001) TRPC1 and TRPC5 form a novel cation channel in mammalian brain. Neuron, 29 (3): 645-55. [PMID:11301024]

29. Strübing C, Krapivinsky G, Krapivinsky L, Clapham DE. (2003) Formation of novel TRPC channels by complex subunit interactions in embryonic brain. J Biol Chem, 278 (40): 39014-9. [PMID:12857742]

30. Tang J, Lin Y, Zhang Z, Tikunova S, Birnbaumer L, Zhu MX. (2001) Identification of common binding sites for calmodulin and inositol 1,4,5-trisphosphate receptors on the carboxyl termini of trp channels. J Biol Chem, 276 (24): 21303-10. [PMID:11290752]

31. Tang Y, Tang J, Chen Z, Trost C, Flockerzi V, Li M, Ramesh V, Zhu MX. (2000) Association of mammalian trp4 and phospholipase C isozymes with a PDZ domain-containing protein, NHERF. J Biol Chem, 275 (48): 37559-64. [PMID:10980202]

32. Tsvilovskyy VV, Zholos AV, Aberle T, Philipp SE, Dietrich A, Zhu MX, Birnbaumer L, Freichel M, Flockerzi V. (2009) Deletion of TRPC4 and TRPC6 in mice impairs smooth muscle contraction and intestinal motility in vivo. Gastroenterology, 137 (4): 1415-24. [PMID:19549525]

33. Walker RL, Koh SD, Sergeant GP, Sanders KM, Horowitz B. (2002) TRPC4 currents have properties similar to the pacemaker current in interstitial cells of Cajal. Am J Physiol, Cell Physiol, 283 (6): C1637-45. [PMID:12388058]

34. Zechel S, Werner S, von Bohlen Und Halbach O. (2007) Distribution of TRPC4 in developing and adult murine brain. Cell Tissue Res, 328 (3): 651-6. [PMID:17345099]

35. Zhu Y, Lu Y, Qu C, Miller M, Tian J, Thakur DP, Zhu J, Deng Z, Hu X, Wu M et al.. (2015) Identification and optimization of 2-aminobenzimidazole derivatives as novel inhibitors of TRPC4 and TRPC5 channels. Br J Pharmacol, 172 (14): 3495-509. [PMID:25816897]

Contributors

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