TRPC4

Target id: 489

Nomenclature: TRPC4

Family: Transient Receptor Potential channels

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 :     Currently no data for TRPC4 in GtoImmuPdb

Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 977 13q13.1-q13.2 TRPC4 transient receptor potential cation channel subfamily C member 4
Mouse 6 1 974 3 D 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
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
CATH/Gene3D
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
TRPC1 23
TRPC3 24
TRPC5 23
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
calmodulin 25
NHERF 26
MxA 10
IP3R3 25
caveolin-1 14
D2 receptor 6
i2 8
STIM1 7
ZO-1 21
SESTD1 12
αII-spectrin 15
Functional Characteristics
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
Species:  Mouse
Rank order:  Ca2+ = Na+
References:  19,23
Other chemical activators (Human)
NO-mediated cysteine S-nitrosylation, potentiation by extracellular protons

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

Activators
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
La3+ 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 [20]. Intracellular calcium potentiates TRPC4β [2].
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
(-)-englerin A Hs Agonist - - 1
[1]
Channel Blockers
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
niflumic acid Mm Antagonist - - 3x10-5 -60.0 28
Conc range: 3x10-5 M [28]
Holding voltage: -60.0 mV
ML204 Mm Inhibition 5.5 pIC50 - - 13
pIC50 5.5 (IC50 2.91x10-6 M) [13]
2-APB Hs - - - - -
La3+ Hs - - - - -
mM range
SKF96365 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 [16].
Tissue Distribution
Heart, brain, pancreas, placenta, kidney.
Species:  Human
Technique:  Northern Blot
References:  11
Arterial endothelial cells and smooth muscle cells
Species:  Human
Technique:  Immunohistochemistry
References:  29
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:  18
Hippocampal CA1 & CA3 areas, dentate gyrus.
Species:  Rat
Technique:  Immunohistochemistry
References:  9
Functional Assays
Nonselective cation current activated by Gq stimulation.
Species:  Mouse
Tissue:  Heterologous expression.
Response measured:  Cation current.
References:  19,23
Physiological Functions
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:  9
Heteromer of TRPC1/C4 contributes to seizure activity in lateral septal neurons.
Species:  Mouse
Tissue:  Brain: septum
References:  17
Heteromer of TRPC1/C4 contributes to synaptic responses in olfactory bulb neurons.
Species:  Mouse
Tissue:  Brain: olfactory bulb.
References:  22
Contributes to muscarinic activated current in gastric smooth muscle cells.
Species:  Mouse
Tissue:  Gastrointestinal smooth muscle cells.
References:  27
Phenotypes, Alleles and Disease Models 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
Type:  Splice variant
Species:  Rat
Description:  β-isoform
Amino acids:  893
Nucleotide accession: 
Protein accession: 
Type:  Splice variant
Species:  Rat
Description:  α-isoform
Amino acids:  977
Nucleotide accession: 
Protein accession: 
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 [23].

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, Hofmann F, Flockerzi V, Nilius B. (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. Acta1778 (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. 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. Cells20 (3): 435-41. [PMID:16404161]

10. 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]

11. McKay RR, Szymeczek-Seay CL, Lievremont JP, Bird GS, Zitt C, Jungling E, Luckhoff A, Putney 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

19. 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]

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

21. 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. Glia49 (3): 418-29. [PMID:15540229]

22. 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]

23. Strübing C, Krapivinsky G, Krapivinsky L, Clapham DE. (2001) TRPC1 and TRPC5 form a novel cation channel in mammalian brain. Neuron29 (3): 645-55. [PMID:11301024]

24. 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]

25. 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]

26. 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]

27. 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. Gastroenterology137 (4): 1415-24. [PMID:19549525]

28. 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]

29. 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]

Contributors

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How to cite this page

Nathaniel T Blair, David E. Clapham.
Transient Receptor Potential channels: TRPC4. Last modified on 24/04/2017. Accessed on 26/04/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=489.