TRPC4

Summary

TRPC4 (transient receptor potential cation channel subfamily C member 4, HGNC:12336) is a protein-coding gene on chromosome 13q13.3, encoding Short transient receptor potential channel 4 (Q9UBN4). Forms a receptor-activated non-selective calcium permeant cation channel.

This gene encodes a member of the canonical subfamily of transient receptor potential cation channels. The encoded protein forms a non-selective calcium-permeable cation channel that is activated by Gq-coupled receptors and tyrosine kinases, and plays a role in multiple processes including endothelial permeability, vasodilation, neurotransmitter release and cell proliferation. Single nucleotide polymorphisms in this gene may be associated with generalized epilepsy with photosensitivity. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 7223 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 105 total — 1 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_016179

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12336
Approved symbol	TRPC4
Name	transient receptor potential cation channel subfamily C member 4
Location	13q13.3
Locus type	gene with protein product
Status	Approved
Aliases	HTRP4, TRP4
Ensembl gene	ENSG00000133107
Ensembl biotype	protein_coding
OMIM	603651
Entrez	7223

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 10 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000338947, ENST00000355779, ENST00000358477, ENST00000379673, ENST00000379679, ENST00000379705, ENST00000426868, ENST00000488717, ENST00000494529, ENST00000625583, ENST00000957123, ENST00000957124

RefSeq mRNA: 9 — MANE Select: NM_016179 NM_001135955, NM_001135956, NM_001135957, NM_001135958, NM_001354799, NM_001354806, NM_001372055, NM_003306, NM_016179

CCDS: CCDS45035, CCDS45036, CCDS45037, CCDS45038, CCDS45039, CCDS9365

Canonical transcript exons

ENST00000379705 — 11 exons

Exon	Start	End
ENSE00000907457	37691999	37692335
ENSE00000907458	37745937	37746455
ENSE00001136917	37782956	37783360
ENSE00001425129	37869595	37869772
ENSE00001847458	37632063	37637625
ENSE00003473790	37639040	37639129
ENSE00003523486	37639258	37639299
ENSE00003586933	37651265	37651459
ENSE00003590739	37674228	37674367
ENSE00003640382	37655088	37655283
ENSE00003683912	37663416	37663729

Expression profiles

Bgee: expression breadth ubiquitous, 158 present calls, max score 86.21.

FANTOM5 (CAGE): breadth broad, TPM avg 2.0502 / max 68.3181, expressed in 557 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
136863	1.9089	536
136864	0.1413	74

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	86.21	gold quality
decidua	UBERON:0002450	83.03	gold quality
smooth muscle tissue	UBERON:0001135	82.70	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.54	gold quality
body of uterus	UBERON:0009853	80.03	gold quality
right coronary artery	UBERON:0001625	77.55	gold quality
myometrium	UBERON:0001296	77.08	gold quality
parotid gland	UBERON:0001831	76.09	gold quality
triceps brachii	UBERON:0001509	73.10	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	73.07	gold quality
olfactory bulb	UBERON:0002264	72.86	gold quality
left coronary artery	UBERON:0001626	72.71	gold quality
coronary artery	UBERON:0001621	72.52	gold quality
prostate gland	UBERON:0002367	72.45	gold quality
gall bladder	UBERON:0002110	72.35	gold quality
gluteal muscle	UBERON:0002000	72.03	gold quality
heart right ventricle	UBERON:0002080	71.01	gold quality
popliteal artery	UBERON:0002250	71.00	gold quality
tibial artery	UBERON:0007610	70.97	gold quality
seminal vesicle	UBERON:0000998	70.89	gold quality
islet of Langerhans	UBERON:0000006	70.88	gold quality
muscle layer of sigmoid colon	UBERON:0035805	70.83	gold quality
uterus	UBERON:0000995	70.40	gold quality
aorta	UBERON:0000947	69.95	gold quality
pigmented layer of retina	UBERON:0001782	69.90	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	69.82	gold quality
cortical plate	UBERON:0005343	69.78	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	69.76	gold quality
inferior olivary complex	UBERON:0002127	69.65	gold quality
cerebellar vermis	UBERON:0004720	69.30	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.89

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1

miRNA regulators (miRDB)

13 targeting TRPC4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-142-5P	99.48	70.92	2416
HSA-MIR-5590-3P	99.48	70.91	2429
HSA-MIR-7849-3P	99.47	68.17	1224
HSA-MIR-12135	98.99	70.26	1814
HSA-MIR-4709-5P	98.51	67.25	1335
HSA-MIR-624-3P	98.37	67.06	1067
HSA-MIR-6082	96.40	70.86	216

Literature-anchored findings (GeneRIF, showing 40)

• The role of endogenous human Trp4 in regulating carbachol-induced calcium oscillations in HEK-293 cells (PMID:11830588)
• Data demonstrate that the PDZ-interacting domain of TRPC4 controls its localization and surface expression in transfected HEK293 cells. (PMID:12154080)
• may be candidate protein forming store-operated calcium entry channels in term pregnant human myometrium (PMID:12356946)
• Expression of the channel in human esophagogastric junction. (PMID:12736151)
• TRPC channel overexpression may be partially responsible for the increased pulmonary artert smooth muscle cell proliferation and pulmonary vascular medial hypertrophy in pulmonary hypertension patients. (PMID:15358862)
• TRPC4 is implicated in the regulation of calcium homeostasis in astrocytes, particularly as part of a signaling complex that forms at junctional sites between astrocytes. (PMID:15540229)
• TRPC4 is a component of storeoperated channel in human corneal epithelial cells whose activation by EGF is requisite for an optimum mitogenic response to this growth factor (PMID:16033767)
• Two tyrosine residues in the C terminus of human TRPC4 phosphorylated following epidermal growth factor (EGF) receptor stimulation of COS-7 cells. (PMID:16144838)
• interaction of protein 4.1 with TRPC4 is required for activation of the endothelial ISOC channel. (PMID:16254212)
• demonstrates that hTrpC1 and hTrpC4 are the most abundant TrpC mRNAs in human myometrium, with TrpC6 being the next most abundant; these isoforms may play significant roles in signal regulated calcium entry in human myometrium (PMID:16527499)
• TRPC4 is an important component of the I(CRAC)-like channel in human gingival keratinocytes (PMID:17031666)
• platelet capacitative Ca2+ entry channel complexes contain TRPC4 as a molecular component that determines sensitivity of capacitative Ca2+ entry to intracellular alkalosis. (PMID:17074721)
• studies suggest an important role for TRPC4 in supporting Ca2+ entry–{REVIEW} (PMID:17217052)
• TRPC4 channel expression was important for keratinocyte differentiation, as knocking out the channels (by siRNA strategy) prevented the induction of Ca(2+)-induced differentiation. (PMID:17920677)
• Sudy indicates that TRPC4 loss in renal cell carcinoma (RCC) leads to impaired Ca(2+) intake, misfolding, retrograde transport and diminished secretion of antiangiogenic TSP1, thus enabling angiogenic switch during RCC progression. (PMID:18021253)
• results demonstrate that a direct interaction between hTRPC4 and the spectrin cytoskeleton is involved in the regulation of hTRPC4 surface expression and activation (PMID:18048348)
• TRPC1/TRPC4 complexes constitute the functional subunits of SOC and that the interaction between STIM1 and TRPC4 may be the mechanism for the activation of the channels. (PMID:19307462)
• TrpC1 and TrpC4 Regulate Neurite Extension in human embryonic stem cell-Derived Neurons (PMID:19725137)
• Data show that TRPC4 co-precipitated with the junctional proteins beta-catenin and VE-cadherin. (PMID:19996314)
• SESTD1 was found to associate with TRPC4 and TRPC5 via the channel’s calmodulin- and inositol 1,4,5-trisphosphate receptor-binding domain. (PMID:20164195)
• These findings suggest that TNF-R1, TRUSS, and TRPC4 augment Ca(2+) loading of endoplasmic reticulum Ca(2+) stores in the context of m1AchR stimulation (PMID:20458742)
• Results showed a trend toward association of TRPC4 variants and photoparoxysmal response/idiopathic generalized epilepsies. (PMID:20574736)
• Report association of a TRPC4 SNP with myocardial infarction in population-based genetic studies. Higher Ca(2+) signals generated by TRPC4-I957V may facilitate generation of endothelium/nitric oxide-dependent vasorelaxation. (PMID:21427121)
• an essential role of Galpha(i) proteins as novel activators for TRPC4/5 and reveal the molecular mechanism by which G-proteins activate the channels. (PMID:22457348)
• the enhanced apoptosis caused by the simultaneous depletion of Dp53 and Dmp52 is absolutely JNK-dependent. (PMID:23549783)
• the S4-S5 linker is a critical constituent of TRPC4/C5 channel gating and that disturbance of its sequence allows channel opening independent of any sensor domain. (PMID:23677990)
• Tarbp2 binding to TRPC4 promotes changes of cytosolic Ca(2+) and, thereby, leads to a dynamic regulation of Dicer activity, essentially at low endogenous Dicer concentrations. (PMID:24563462)
• The higher amplitude of store-operated Ca2+ entry was associated to the over-expression for Stim2, Orai2-3, and TRPC1 while Stim2 levels remained constant and Stim1, Orai1, Orai3, TRPC1 and TRPC4 proteins were over-expressed in primary myelofibrosis. (PMID:24603752)
• a membrane-targeting domain of the transient receptor potential canonical (TRPC)4 channel unrelated to its formation of a tetrameric structure (PMID:25349210)
• This study identifies a novel role for TRPC4 in the regulation of autophagy in vascular endothelial cells. (PMID:25476892)
• Galpha(i2) activates the TRPC4 channel by direct binding. (PMID:25788576)
• Studies indicate potential roles for Rasd1 small G protein and leptin in TRPC4 cation channel activation. (PMID:26083271)
• slow phase of Gi/o-mediated TRPC4 activation was diminished by inhibiting RhoA or enhancing PLCdelta function (PMID:26755577)
• silencing of TRPC4 alleviates angiogenesis induced by oxidized low-density lipoprotein in human coronary artery endothelial cells through inactivation of VEGF and NF-kappaB. (PMID:26999308)
• STIM1L and TRPC1/4 are working together in myotubes to ensure efficient store refilling and a proper differentiation program. (PMID:28185894)
• These findings suggest identification of an important experimental tool compound, which has much higher potency for inhibiting TRPC1/4/5 channels than previously reported agents, impressive specificity, and graded subtype selectivity within the TRPC1/4/5 channel family. (PMID:28325835)
• Protein levels of TRPC4 were elevated in FCD II and tuberous sclerosis complex cortical samples compared to those of control samples. (PMID:28455787)
• Our results suggest that OGR1-dependent increases in TRPC4 expression may favor formation of highly Ca(2+) -permeable TRPC4-containing channels that promote transformed granule cell migration. Increased motility of cancer cells is a prerequisite for cancer invasion and metastasis, and our findings may point towards a key role for TRPC4 in progression of certain types of medullablastoma. (PMID:28627017)
• We found that the inhibitory Galphai3 protein selectively bound to the G-protein-binding domain on the C-terminus of PC1. The dissociation of Galphai3 upon cleavage of PC1 increased TRPC4 activity. (PMID:29472562)
• Study reports a novel mechanism of self-limiting activation of TRPC1/4 and TRPC1/5 channels by G protein-coupled receptor stimulation. Galphaq protein directly interacts with either TRPC4 or TRPC5 of the heterotetrameric channels to permit activation. Simultaneously, Galphaq-coupled PLCbeta activation leads to the breakdown of PI(4,5)P2, which inhibits activity of TRPC1/4 and 1/5 channels. (PMID:30108272)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	trpc4a	ENSDARG00000070507
danio_rerio	trpc4b	ENSDARG00000102017
mus_musculus	Trpc4	ENSMUSG00000027748
rattus_norvegicus	Trpc4	ENSRNOG00000011133
drosophila_melanogaster	trp	FBGN0003861
drosophila_melanogaster	trpl	FBGN0005614
drosophila_melanogaster	Trpgamma	FBGN0032593
caenorhabditis_elegans		WBGENE00006615

Paralogs (5): TRPC7 (ENSG00000069018), TRPC5 (ENSG00000072315), TRPC6 (ENSG00000137672), TRPC3 (ENSG00000138741), TRPC1 (ENSG00000144935)

Protein

Protein identifiers

Short transient receptor potential channel 4 — Q9UBN4 (reviewed: Q9UBN4)

Alternative names: Trp-related protein 4

All UniProt accessions (2): Q9UBN4, Q3MHB9

UniProt curated annotations — full annotation on UniProt →

Function. Forms a receptor-activated non-selective calcium permeant cation channel. Acts as a cell-cell contact-dependent endothelial calcium entry channel. Forms a homomeric ion channel or a heteromeric ion channel with TRPC1; the heteromeric ion channel has reduced calcium permeability compared to the homomeric channel. Also permeable to monovalent ions including sodium, lithium and cesium ions. Forms a receptor-activated non-selective calcium permeant cation channel.

Subunit / interactions. Homotetramer. Heterotetramer with TRPC1 and/or TRPC5. Forms a heteromeric ion channel with TRPC1, with a 1:3 TRPC1:TRPC4 stoichiometry. Interacts with TRPC4AP. Isoform alpha but not isoform beta interacts with ITPR1, ITPR2 and ITPR3. Interacts with (via PDZ-binding domain) with NHERF1. Interacts with MX1 and RNF24. Interacts (via CIRB domain) with SESTD1 (via spectrin 1 repeat). Interacts with CDH5 and CTNNB1. Interacts with SPTAN1 (via C-terminal spectrin repeats) and SPTBN5 (via C-terminus). Interacts (via protein 4.1-binding domain) with EPB41L2. Interacts with PLSCR1.

Subcellular location. Cell membrane Cell membrane.

Tissue specificity. Strongly expressed in placenta. Expressed at lower levels in heart, pancreas, kidney and brain. Expressed in endothelial cells. Isoform alpha was found to be the predominant isoform. Isoform beta was not found in pancreas and brain.

Post-translational modifications. Phosphorylation modulates TRPC channel function by regulating the level of TRPC4 at the cell surface and by increasing the association with NHERF1.

Activity regulation. May be operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. May be activated by intracellular calcium store depletion. Inhibited by xanthine-based inhibitor Pico145.

Domain organisation. The protein 4.1-binding domain (654-685) is required for binding to EPB41L2 and channel activation. The calmodulin- and inositol 1,4,5-trisphosphate receptor-binding (CIRB) domain (695-724) is sufficient for the interaction with SESTD1. The spectrin-binding domain (730-758) is required for binding to SPTAN1 and SPTBN5.

Miscellaneous. The interaction with spectrin is important in controlling the translocation of TRPC4 channels to the plasma membrane following EGF stimulation. The cell membrane presentation, the calcium entry function and the interaction with junctional proteins (CTNNB1 and CDH5) are controlled by endothelial cell-cell contacts.

Similarity. Belongs to the transient receptor (TC 1.A.4) family. STrpC subfamily. TRPC4 sub-subfamily.

Isoforms (7)

UniProt ID	Names	Canonical?
Q9UBN4-1	Alpha	yes
Q9UBN4-2	Beta
Q9UBN4-3	Delta
Q9UBN4-4	Gamma
Q9UBN4-5	Epsilon
Q9UBN4-6	Zeta
Q9UBN4-7	Eta

RefSeq proteins (9): NP_001129427, NP_001129428, NP_001129429, NP_001129430, NP_001341728, NP_001341735, NP_001358984, NP_003297, NP_057263* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR002153	TRPC_channel	Family
IPR005460	TRPC4_channel	Family
IPR005821	Ion_trans_dom	Domain
IPR013555	TRP_dom	Domain
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF00023, PF00520, PF08344, PF12796

Catalyzed reactions (Rhea), 4 shown:

• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• Na(+)(in) = Na(+)(out) (RHEA:34963)
• Li(+)(in) = Li(+)(out) (RHEA:78551)
• Cs(+)(in) = Cs(+)(out) (RHEA:78555)

UniProt features (98 total): helix 36, topological domain 8, binding site 8, strand 8, splice variant 7, transmembrane region 6, turn 6, repeat 4, region of interest 3, mutagenesis site 3, compositionally biased region 2, modified residue 2, chain 1, intramembrane region 1, coiled-coil region 1, disulfide bond 1, sequence variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8WPN	ELECTRON MICROSCOPY	2.82
8WPL	ELECTRON MICROSCOPY	3.04
8WPM	ELECTRON MICROSCOPY	3.43

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBN4-F1	74.71	0.43

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (8): 172; 176; 178; 181; 417; 420; 435; 438

Post-translational modifications (2): 959, 972

Disulfide bonds (1): 549–554

Mutagenesis-validated functional residues (3):

Position	Phenotype
959	reduced egf-induced phosphorylation and decreased association with nherf1. loss of egf-induced phosphorylation and decre
972	reduced egf-induced phosphorylation and decreased association with nherf1. loss of egf-induced phosphorylation and decre
975–977	loss of interaction with nherf1.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3295583	TRP channels
R-HSA-418890	Role of second messengers in netrin-1 signaling

MSigDB gene sets: 150 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, RNGTGGGC_UNKNOWN, FREAC2_01, GOBP_ACID_SECRETION, GCANCTGNY_MYOD_Q6, TTTGTAG_MIR520D, GOCC_CELL_SURFACE, AP4_Q6, GOBP_NEUROGENESIS, CAGCTG_AP4_Q5, chr13q13, GOBP_MONOATOMIC_CATION_TRANSPORT, AACWWCAANK_UNKNOWN, GOBP_ORGANIC_ACID_TRANSPORT, FREAC3_01

GO Biological Process (9): calcium ion transport (GO:0006816), gamma-aminobutyric acid secretion (GO:0014051), oligodendrocyte differentiation (GO:0048709), regulation of cytosolic calcium ion concentration (GO:0051480), calcium ion import (GO:0070509), calcium ion transmembrane transport (GO:0070588), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (7): calcium channel activity (GO:0005262), beta-catenin binding (GO:0008013), store-operated calcium channel activity (GO:0015279), cadherin binding (GO:0045296), inositol 1,4,5 trisphosphate binding (GO:0070679), monoatomic ion channel activity (GO:0005216), protein binding (GO:0005515)

GO Cellular Component (11): plasma membrane (GO:0005886), caveola (GO:0005901), cell surface (GO:0009986), basolateral plasma membrane (GO:0016323), cortical cytoskeleton (GO:0030863), cation channel complex (GO:0034703), calcium channel complex (GO:0034704), cell-cell junction (GO:0005911), membrane (GO:0016020), protein-containing complex (GO:0032991), membrane raft (GO:0045121)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Stimuli-sensing channels	1
Netrin-1 signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
calcium ion transport	2
transport	2
cellular anatomical structure	2
metal ion transport	1
gamma-aminobutyric acid transport	1
acid secretion	1
central nervous system development	1
glial cell differentiation	1
intracellular calcium ion homeostasis	1
monoatomic cation transmembrane transport	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
protein binding	1
calcium channel activity	1
cell adhesion molecule binding	1
anion binding	1
alcohol binding	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
binding	1
membrane	1
cell periphery	1
plasma membrane raft	1
basal plasma membrane	1
plasma membrane region	1
cytoskeleton	1
cell cortex	1
monoatomic ion channel complex	1
cation channel complex	1
anchoring junction	1
cellular_component	1
membrane microdomain	1

Protein interactions and networks

STRING

1316 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRPC4	TRPC1	P48995	982
TRPC4	TRPC3	Q13507	973
TRPC4	STIM1	Q13586	971
TRPC4	TRPC5	Q9UL62	970
TRPC4	NHERF1	O14745	920
TRPC4	ORAI1	Q96D31	883
TRPC4	TRPV4	Q9HBA0	867
TRPC4	ORAI3	Q9BRQ5	825
TRPC4	ORAI2	Q96SN7	825
TRPC4	STIM2	Q9P246	816
TRPC4	SESTD1	Q86VW0	805
TRPC4	PKD1	P98161	803
TRPC4	CAV1	Q03135	792
TRPC4	TRPA1	O75762	768
TRPC4	ANK1	P16157	739

IntAct

7 interactions, top by confidence:

A	B	Type	Score
TRPC4	ITPR2	psi-mi:“MI:0915”(physical association)	0.530
TRPC4	ITPR2	psi-mi:“MI:0407”(direct interaction)	0.530
MX1	TRPC4	psi-mi:“MI:0915”(physical association)	0.520
TRPC4	MX1	psi-mi:“MI:0915”(physical association)	0.520
TRPC4	PHB1	psi-mi:“MI:0915”(physical association)	0.400
TRPC4	USP13	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (28): TRPC4 (Affinity Capture-Western), TRPC4 (Affinity Capture-Western), TRPC3 (Affinity Capture-Western), TRPC6 (Affinity Capture-Western), TRPC1 (Affinity Capture-Western), TRPC4 (Reconstituted Complex), TRPC4 (Affinity Capture-Western), FKBP4 (Affinity Capture-Western), TRPC4 (Affinity Capture-MS), TRPC4 (Affinity Capture-Western), TRPC4 (Affinity Capture-Western), TRPC4 (Affinity Capture-Western), TRPC4 (FRET), TRPC4 (FRET), TRPC5 (FRET)

ESM2 similar proteins: A0A0R4IDX9, A0A2C9VBV6, A2ARJ3, A7T1N0, A7Y2X0, A8Y2U2, O12977, O17386, O35119, O70131, O76689, O80739, P31662, P52166, P70617, P79100, Q05005, Q08469, Q0WMJ8, Q3UP23, Q57UM0, Q5JK32, Q5R9C2, Q5W0B7, Q69RI8, Q6H4R6, Q6NPT7, Q6ZUK4, Q75G84, Q84MS3, Q84MS4, Q8BG16, Q8BJI1, Q8MPP0, Q90X07, Q92982, Q94KB1, Q94KB9, Q9FI00, Q9FY75

Diamond homologs: O18784, O35119, O62826, O62852, P19334, P34586, P48994, P48995, P79100, Q13507, Q61056, Q61143, Q9HCX4, Q9JMI9, Q9MYV9, Q9MYW0, Q9QUQ5, Q9QX01, Q9QX29, Q9QZC1, Q9R244, Q9R283, Q9TUN9, Q9UBN4, Q9UL62, Q9VJJ7, Q9WVC5, Q9Y210, Q6IVV8, O54935, P18887, Q60596, Q6ZNB5, Q9ESZ0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ITCH	“down-regulates activity”	TRPC4	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

105 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	86
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2571615	NM_016179.4(TRPC4):c.379-2A>T	Pathogenic

SpliceAI

2855 predictions. Top by Δscore:

Variant	Effect	Δscore
13:37637637:T:C	acceptor_gain	1.0000
13:37639035:GTTA:G	donor_loss	1.0000
13:37639036:TTA:T	donor_loss	1.0000
13:37639037:TA:T	donor_loss	1.0000
13:37639038:A:AG	donor_loss	1.0000
13:37639039:CCTT:C	donor_loss	1.0000
13:37639136:CAT:C	acceptor_gain	1.0000
13:37639137:A:C	acceptor_gain	1.0000
13:37639138:T:TC	acceptor_gain	1.0000
13:37639139:T:C	acceptor_gain	1.0000
13:37639140:T:C	acceptor_gain	1.0000
13:37639140:T:TC	acceptor_gain	1.0000
13:37639254:TTACT:T	donor_loss	1.0000
13:37639255:TACT:T	donor_loss	1.0000
13:37639256:A:AC	donor_gain	1.0000
13:37639256:A:C	donor_loss	1.0000
13:37639257:C:CA	donor_loss	1.0000
13:37639257:C:CC	donor_gain	1.0000
13:37651249:CATG:C	donor_gain	1.0000
13:37651263:AC:A	donor_gain	1.0000
13:37651263:ACC:A	donor_gain	1.0000
13:37651264:CC:C	donor_gain	1.0000
13:37651264:CCC:C	donor_gain	1.0000
13:37651455:TGGTC:T	acceptor_gain	1.0000
13:37655086:A:AC	donor_gain	1.0000
13:37655087:C:CC	donor_gain	1.0000
13:37655087:CAG:C	donor_gain	1.0000
13:37671945:T:A	donor_gain	1.0000
13:37674223:GTTAC:G	donor_loss	1.0000
13:37674224:TTAC:T	donor_loss	1.0000

AlphaMissense

6423 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:37637597:C:G	R747P	1.000
13:37637617:C:A	K740N	1.000
13:37637617:C:G	K740N	1.000
13:37637621:A:G	L739P	1.000
13:37639113:A:G	L713P	1.000
13:37651417:A:G	W643R	1.000
13:37651417:A:T	W643R	1.000
13:37651419:A:G	L642P	1.000
13:37651433:A:C	F637L	1.000
13:37651433:A:T	F637L	1.000
13:37651435:A:G	F637L	1.000
13:37651439:C:A	W635C	1.000
13:37651439:C:G	W635C	1.000
13:37651440:C:G	W635S	1.000
13:37651441:A:G	W635R	1.000
13:37651441:A:T	W635R	1.000
13:37655104:G:A	S623F	1.000
13:37655119:G:T	A618D	1.000
13:37655122:A:T	I617K	1.000
13:37655130:G:C	N614K	1.000
13:37655130:G:T	N614K	1.000
13:37655134:A:G	L613P	1.000
13:37655137:A:G	L612P	1.000
13:37655140:A:T	V611D	1.000
13:37655167:C:T	G602E	1.000
13:37655168:C:G	G602R	1.000
13:37655168:C:T	G602R	1.000
13:37655182:C:T	G597D	1.000
13:37655183:C:G	G597R	1.000
13:37655185:A:T	V596D	1.000

dbSNP variants (sampled 300 via entrez): RS1000015292 (13:37705023 A>G), RS1000015902 (13:37723361 A>G), RS1000018976 (13:37827450 G>T), RS1000021881 (13:37745725 T>G), RS1000022211 (13:37707212 C>G,T), RS1000028116 (13:37747713 A>G), RS1000060229 (13:37677396 T>A,C), RS1000067554 (13:37704615 A>G), RS1000088654 (13:37791693 C>A,T), RS1000134411 (13:37840645 T>C), RS1000134565 (13:37829075 G>C), RS1000155674 (13:37751517 T>C), RS1000162668 (13:37711878 A>G), RS1000163779 (13:37671347 G>A), RS1000172907 (13:37751881 G>A)

Disease associations

OMIM: gene MIM:603651 | disease phenotypes: MIM:209850

GenCC curated gene-disease

Mondo (2): prostate cancer (MONDO:0008315), autism, susceptiblity to (MONDO:0020836)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001762_436	Obesity-related traits	9.000000e-06
GCST001762_440	Obesity-related traits	9.000000e-06
GCST001814_20	Age-related macular degeneration	6.000000e-06
GCST001814_30	Age-related macular degeneration	6.000000e-06
GCST002682_12	Tourette’s syndrome or obsessive-compulsive disorder	6.000000e-06
GCST003124_12	Mild influenza (H1N1) infection	2.000000e-08
GCST004250_29	Alanine aminotransferase (ALT) levels after remission induction therapy in actute lymphoblastic leukemia (ALL)	1.000000e-06
GCST007603_11	Smoking initiation	4.000000e-08
GCST008810_91	Smoking initiation (ever regular vs never regular)	2.000000e-08
GCST011703_14	Smoking initiation	5.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005106	body composition measurement
EFO:1001488	influenza A (H1N1)
EFO:0007965	response to combination chemotherapy
EFO:0005670	smoking initiation

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4295971 (SINGLE PROTEIN), CHEMBL4523661 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 50 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL4466522	ZERENCOTREP	2	50

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: vgic — Transient Receptor Potential channels (TRP)

Most potent curated ligand interactions (7 total), top 7:

Ligand	Action	Affinity	Parameter
Pico145	Inhibition	9.46	pIC50
(-)-englerin A	Agonist	7.95	pEC50
HC-070	Antagonist	7.34	pIC50
tonantzitlolone	Activation	6.91	pEC50
ML204	Channel blocker	5.5	pIC50
M084	Inhibition	5.27	pIC50
clemizole	Channel blocker	5.19	pIC50

ChEMBL bioactivities

13 potent at pChembl≥5 of 15 total, top 11 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.92	IC50	0.012	nM	ZERENCOTREP
10.52	IC50	0.03	nM	ZERENCOTREP
10.48	IC50	0.033	nM	ZERENCOTREP
9.47	IC50	0.34	nM	ZERENCOTREP
7.75	IC50	18	nM	CHEMBL4752870
7.35	IC50	45	nM	CHEMBL5597024
7.34	IC50	46	nM	CHEMBL4546097
7.21	IC50	62	nM	CHEMBL4450705
7.19	IC50	65	nM	CHEMBL5201831
6.54	IC50	290	nM	CHEMBL4530872
5.69	IC50	2060	nM	CHEMBL5207902

PubChem BioAssay actives

11 with measured affinity, of 40 total; 8 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-3-methyl-8-[3-(trifluoromethoxy)phenoxy]purine-2,6-dione	1578709: Inhibition of human TRPC4/human TRPC1 expressed in HEK293 cells assessed as reduction in englerin A-induced calcium entry incubated for 30 mins by Fluo-4AM dye based fluorescence assay	ic50	<0.0001	uM
5-chloro-4-[4-[4-fluoro-2-(trifluoromethyl)phenoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-1H-pyridazin-6-one	2119897: Inhibition of TRPC4 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.0180	uM
5-chloro-4-[3-[(2-chloro-4-fluorophenyl)-methoxymethyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-1H-pyridazin-6-one	2119897: Inhibition of TRPC4 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.0450	uM
8-(3-chlorophenoxy)-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-3-methylpurine-2,6-dione	1578713: Inhibition of human TRPC4 expressed in human T-REx-293 cells coexpressing M1 receptor assessed as reduction in calcium influx by Fluo-4AM dye based assay	ic50	0.0460	uM
[(1R,2R,5R,6R,7S,8S,10R)-10-(2-hydroxyethoxy)-1,5-dimethyl-8-propan-2-yl-11-oxatricyclo[6.2.1.02,6]undecan-7-yl] (E)-3-phenylprop-2-enoate	1578692: Antagonist activity at TRPC4/TRPC1 in human A498 cells assessed as reduction in englerin A-induced calcium entry preincubated for 30 mins followed by englerin A addition by fluorescence method	ic50	0.0620	uM
3-chloro-4-[4-[4-fluoro-2-(trifluoromethyl)phenoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]pyrrole-2,5-dione	1889506: Inhibition of TRPC4 channel (unknown origin) expressed in HEK293 cells assessed as inhibition of EA-evoked Ca2+ entry by measuring reduction in intracellular Ca2+ level by Fluo-4 dye based FLIPR assay	ic50	0.0650	uM
5-chloro-4-[3-oxo-4-[[2-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]-1H-pyridazin-6-one	1611667: Inhibition of Englerin-activated human TRPC4 channel expressed in HEK293 cells by Q-patch clamp assay	ic50	0.2900	uM
1-benzyl-5-ethyl-N-(furan-2-ylmethyl)benzimidazol-2-amine	1873793: Inhibition of human TRPC4 channel expressed in HEK293 cells assessed as inhibition of EA-evoked Calcium influx by measuring reduction in intracellular Ca2+ level and measured upto 360 sec by Fluo-4/AM dye based FLIPR assay	ic50	2.0600	uM

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	4
trichostatin A	affects cotreatment, decreases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Barium	affects reaction, increases transport	2
Carbachol	increases transport, increases response to substance, increases activity, affects reaction	2
Doxorubicin	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
p-Chloromercuribenzoic Acid	decreases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
sodium arsenite	decreases expression	1
zinc chromate	increases abundance, decreases expression	1
potassium chromate(VI)	decreases expression	1
1-oleoyl-2-acetylglycerol	affects reaction, increases transport	1
arsenic disulfide	increases methylation	1
chromium hexavalent ion	decreases expression, increases abundance	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
3,4,5,4’-tetramethoxystilbene	affects expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Vorinostat	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Calcium	affects reaction, increases transport	1
Catechin	decreases expression, affects cotreatment	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Malathion	decreases expression	1
Progesterone	increases expression	1

ChEMBL screening assays

22 unique, capped per target: 18 binding, 4 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4158454	Binding	Inhibition of TRPC4 (unknown origin)	Discovery of Pyrrolidine Sulfonamides as Selective and Orally Bioavailable Antagonists of Transient Receptor Potential Vanilloid-4 (TRPV4). — J Med Chem
CHEMBL4622714	ADMET	Agonist activity at human TRPC4/TRPC1 expressed in HEK293 Tet cells assessed as increase in intracellular calcium level at 1 uM measured at 5 secs interval for 300 secs by Fura-2AM dye based fluorescence assay	Bridgehead Modifications of Englerin A Reduce TRPC4 Activity and Intravenous Toxicity but not Cell Growth Inhibition. — ACS Med Chem Lett

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer