TRPC6

Summary

TRPC6 (transient receptor potential cation channel subfamily C member 6, HGNC:12338) is a protein-coding gene on chromosome 11q22.1, encoding Short transient receptor potential channel 6 (Q9Y210). Forms a receptor-activated non-selective calcium permeant cation channel.

The protein encoded by this gene forms a receptor-activated calcium channel in the cell membrane. The channel is activated by diacylglycerol and is thought to be under the control of a phosphatidylinositol second messenger system. Activation of this channel occurs independently of protein kinase C and is not triggered by low levels of intracellular calcium. Defects in this gene are a cause of focal segmental glomerulosclerosis 2 (FSGS2).

Source: NCBI Gene 7225 — RefSeq curated summary.

At a glance

• Gene–disease (curated): focal segmental glomerulosclerosis 2 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 11
• Clinical variants (ClinVar): 574 total — 7 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004621

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12338
Approved symbol	TRPC6
Name	transient receptor potential cation channel subfamily C member 6
Location	11q22.1
Locus type	gene with protein product
Status	Approved
Aliases	TRP6
Ensembl gene	ENSG00000137672
Ensembl biotype	protein_coding
OMIM	603652
Entrez	7225

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000344327, ENST00000348423, ENST00000360497, ENST00000526713, ENST00000527240, ENST00000532133, ENST00000532184, ENST00000893220, ENST00000893221, ENST00000962874

RefSeq mRNA: 1 — MANE Select: NM_004621 NM_004621

CCDS: CCDS8311

Canonical transcript exons

ENST00000344327 — 13 exons

Exon	Start	End
ENSE00000930263	101453650	101453725
ENSE00000930264	101455018	101455101
ENSE00000930265	101469427	101469501
ENSE00000930266	101471183	101471386
ENSE00000930267	101472137	101472332
ENSE00000930268	101473509	101473773
ENSE00001097722	101482949	101483165
ENSE00001097723	101491556	101491738
ENSE00001097724	101488937	101489101
ENSE00001097725	101504024	101504798
ENSE00001097731	101476301	101476534
ENSE00001368794	101583334	101584007
ENSE00001382995	101451564	101453106

Expression profiles

Bgee: expression breadth ubiquitous, 180 present calls, max score 91.26.

FANTOM5 (CAGE): breadth broad, TPM avg 1.1650 / max 130.0533, expressed in 413 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121944	0.6681	299
121947	0.2611	118
121948	0.1415	82
121945	0.0365	16
121946	0.0270	10
121942	0.0176	6
121943	0.0130	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	91.26	gold quality
lower esophagus muscularis layer	UBERON:0035833	84.46	gold quality
lower esophagus	UBERON:0013473	84.41	gold quality
upper lobe of left lung	UBERON:0008952	83.85	gold quality
upper lobe of lung	UBERON:0008948	83.04	gold quality
right uterine tube	UBERON:0001302	82.00	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.46	gold quality
left lobe of thyroid gland	UBERON:0001120	79.22	gold quality
right lobe of thyroid gland	UBERON:0001119	78.94	gold quality
calcaneal tendon	UBERON:0003701	78.61	gold quality
thyroid gland	UBERON:0002046	78.39	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	78.28	gold quality
lung	UBERON:0002048	77.15	gold quality
stromal cell of endometrium	CL:0002255	76.62	gold quality
visceral pleura	UBERON:0002401	74.40	gold quality
esophagus	UBERON:0001043	74.32	gold quality
subcutaneous adipose tissue	UBERON:0002190	74.25	gold quality
muscle layer of sigmoid colon	UBERON:0035805	73.49	gold quality
omental fat pad	UBERON:0010414	72.93	gold quality
peritoneum	UBERON:0002358	72.85	gold quality
body of uterus	UBERON:0009853	72.20	gold quality
smooth muscle tissue	UBERON:0001135	72.02	gold quality
endocervix	UBERON:0000458	71.40	gold quality
lower esophagus mucosa	UBERON:0035834	71.32	gold quality
adipose tissue of abdominal region	UBERON:0007808	71.22	gold quality
placenta	UBERON:0001987	70.83	gold quality
colonic epithelium	UBERON:0000397	70.61	gold quality
gall bladder	UBERON:0002110	70.31	gold quality
ectocervix	UBERON:0012249	70.19	gold quality
ventricular zone	UBERON:0003053	70.17	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.03

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): JUN, NFKB1, NFKB, RELA, SRF, STAT3, TP53, VDR

miRNA regulators (miRDB)

75 targeting TRPC6, 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-190A-3P	100.00	80.35	5520
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-4517	99.76	69.19	1867

Literature-anchored findings (GeneRIF, showing 40)

• T-cells express a diacylglycerol-activated cation channel, unrelated to the channel involved in capacitative Ca(2+) entry, and associated with the expression of TRP6 protein (PMID:11988098)
• an examination of subunits in living cells (PMID:12032305)
• expresssed in platelets: forms the store-independent calcium entry channel (PMID:12351388)
• 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)
• Data demonstrate the expression of transient receptor potential channel 6 (TRPC6) and a range of homologs in the airway and the presence of a functional Ca(2+) entry pathway with characteristics typical of TRPC family members. (PMID:12871853)
• the pattern of TRPC3 and TRPC6 glycosylation determines regulation of their activity (PMID:12970363)
• an exocytotic mechanism is involved in the activation of TRPC6 (PMID:14662757)
• TRPC6 channels are activated by receptor stimulation (PMID:15023993)
• 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)
• Data suggest that the link between transient receptor potential channel 6 and phosphatidylinositol 3,4,5-trisphosphate-mediated calcium entry may be involved in initiating calcium response to agonist stimulation in T cells. (PMID:15362854)
• TRPC3/TRPC6 channels are localized to the apical region of polarized epithelial cells, which in salivary gland ducts could contribute to the regulation of salivary [Ca2+] and secretion [TRPC6] (PMID:15623527)
• a family with familial focal segmental glomerulosclerosis carries a missense mutation in TRPC6; the proline-to-glutamine substitution enhances TRPC6-mediated calcium signals in response to agonists & appears to alter intracellular distribution of TRPC6 (PMID:15879175)
• the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm. (PMID:15924139)
• Mutation on chromosome 11 may be involved in focal sclerosing glomerulonephritis. (PMID:15998650)
• study suggests that the lysophosphatidylcholine increases calcium in corporal smooth muscle cells probably through activation of a transcript of transient receptor potential channel 6 (TRPC6) channel (PMID:16034470)
• in cells exhibiting a high input resistance, the primary effect of activating TRPC6 will be membrane depolarization (PMID:16439426)
• 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)
• Biochemical and functional evidence supporting the view that heteromultimeric TRPC6-TRPC7 channels contribute to receptor-activated, nonselective cation channels of A7r5 vascular smooth muscle cells. (TRPC6 and TRPC7 channels) (PMID:16690880)
• In this review, the known roles of TRPC6 in the kidney and other organ systems are used as a framework to discuss possible signaling pathways that TRPC6 may modulate during normal glomerular function and in disease states. (PMID:17116414)
• Galphaq activation of TRPC6 signals the activation of PKCalpha, and thereby induces RhoA activity and endothelial cell contraction (PMID:17197445)
• TRPC6 was identified as an essential component of the slit diaphragm architecture of kidney podocytes–{review} (PMID:17217054)
• TRPC6 bound directly to phosphoinositides, and with highest potency to phosphatidylinositol 3,4,5-trisphosphate (PIP(3)). PIP(3) binding disrupted the association of calmodulin (CaM) with TRPC6. (PMID:17317623)
• Orai1 physically interacts with the N and C termini of TRPC3 and TRPC6 (PMID:17360584)
• Snapin links the alpha(1A)-AR to TRPC6, augmenting Ca(2+) influx via ROC channels (PMID:17684020)
• TRPC6 protein expression in glomerular mesangial cells (MCs) was downregulated by high glucose and the deficiency of TRPC6 protein might contribute to the impaired Ca(2+) signaling of MCs seen in diabetes. (PMID:17699555)
• Phosphatidylinositol 4,5-bisphosphate enhances store-operated Ca2+ entry in human platelets, most probably by stimulation of hTRPC6 channels (PMID:17719101)
• mitochondria limit the cytosolic diffusion of localized Na+ transients generated by agonist-mediated activation of transient receptor potential channel 6-containing channels (PMID:17872462)
• functional expression of TRPC6 in mammalian stretch-activated mechano-sensitive Ca(2+) permeable cation channels remains problematic (PMID:17957383)
• Human and mouse erythrocytes express TRPC6 cation channels which participate in cation leak and Ca(2+)-induced suicidal death. (PMID:18209485)
• tested the hypothesis that hyperglycemia increases the expression of TRPC6 channels (PMID:18258814)
• data show that calcium influx in HL-60 cells relies on TRPC channels 1,3, and 6, and Orai1 for allowing NADPH oxidase activation (PMID:18436303)
• analysis of a TRPC6-TRPC5 channel cascade that restricts endothelial cell movement (PMID:18495872)
• TRPC6 was very weakly expressed in isolated hepatocytes from healthy patients and expressed more strongly in tumoral samples from the liver of a cancer patient, strongly supporting a role for these calcium channels in liver oncogenesis. (PMID:18506892)
• These results strongly suggest that TRPC6 channels can be negatively regulated by the nitric oxide-cyclic GMP-protein kinase G pathway, probably via T69 phosphorylation of the N-terminal. (PMID:18617565)
• Mutations have been identified as the cause for progressive kidney failure with urinary protein loss. (PMID:18784209)
• TRPC6 is an obligatory component of cation channels required for the VEGF-mediated increase in cytosolic calcium and subsequent downstream signaling that leads to processes associated with angiogenesis (PMID:18800249)
• TRPC6 activation is sufficient to induce keratinocyte differentiation similar to the physiological stimulus Ca(2+) (PMID:18818211)
• Two calcium2+-permeable members of the TRPC family of cation channels, TRPC3 and TRPC6, can interact with the pore-forming subunits of BKCa channels in podocytes and in heterologous systems in which both classes of channels are transiently expressed. (PMID:19052171)
• TRPC6 regulates TRPC3 activation by Epo (PMID:19074769)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	trpc6a	ENSDARG00000056625
danio_rerio	trpc6b	ENSDARG00000067730
mus_musculus	Trpc6	ENSMUSG00000031997
rattus_norvegicus	Trpc6	ENSRNOG00000006324
caenorhabditis_elegans		WBGENE00006614

Paralogs (5): TRPC7 (ENSG00000069018), TRPC5 (ENSG00000072315), TRPC4 (ENSG00000133107), TRPC3 (ENSG00000138741), TRPC1 (ENSG00000144935)

Protein

Protein identifiers

Short transient receptor potential channel 6 — Q9Y210 (reviewed: Q9Y210)

Alternative names: Transient receptor protein 6

All UniProt accessions (2): Q9Y210, E9PJN4

UniProt curated annotations — full annotation on UniProt →

Function. Forms a receptor-activated non-selective calcium permeant cation channel. Probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Activated by diacylglycerol (DAG) in a membrane-delimited fashion, independently of protein kinase C. Does not seem to be activated by intracellular calcium store depletion.

Subunit / interactions. Homodimer; forms channel complex. Interacts with MX1 and RNF24.

Subcellular location. Cell membrane.

Tissue specificity. Expressed primarily in placenta, lung, spleen, ovary and small intestine. Expressed in podocytes and is a component of the glomerular slit diaphragm.

Post-translational modifications. Phosphorylated by FYN, leading to an increase of TRPC6 channel activity.

Disease relevance. Focal segmental glomerulosclerosis 2 (FSGS2) [MIM:603965] A renal pathology defined by the presence of segmental sclerosis in glomeruli and resulting in proteinuria, reduced glomerular filtration rate and progressive decline in renal function. Renal insufficiency often progresses to end-stage renal disease, a highly morbid state requiring either dialysis therapy or kidney transplantation. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by diacylglycerol (DAG) in a membrane-delimited fashion, independently of protein kinase C.

Similarity. Belongs to the transient receptor (TC 1.A.4) family. STrpC subfamily. TRPC6 sub-subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y210-1	1	yes
Q9Y210-2	2
Q9Y210-3	3

RefSeq proteins (1): NP_004612* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR002153	TRPC_channel	Family
IPR005462	TRPC6_channel	Family
IPR005821	Ion_trans_dom	Domain
IPR013555	TRP_dom	Domain
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF00520, PF08344, PF12796

Catalyzed reactions (Rhea), 1 shown:

• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)

UniProt features (120 total): helix 39, sequence variant 20, strand 14, mutagenesis site 11, turn 8, topological domain 7, transmembrane region 6, repeat 4, sequence conflict 3, glycosylation site 2, splice variant 2, chain 1, region of interest 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
6UZ8	ELECTRON MICROSCOPY	2.84
7DXF	ELECTRON MICROSCOPY	2.9
7DXG	ELECTRON MICROSCOPY	2.9
6UZA	ELECTRON MICROSCOPY	3.08
7A6U	ELECTRON MICROSCOPY	3.62
5YX9	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y210-F1	76.98	0.34

Functional residue map

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

Post-translational modifications (1): 815

Glycosylation sites (2): 473, 561

Mutagenesis-validated functional residues (11):

Position	Phenotype
110	increases calcium ion transport.
125	no effect on rnf24-binding; when associated with a-127; a-128 and a-130.
127	no effect on rnf24-binding; when associated with a-125; a-128 and a-130.
128	no effect on rnf24-binding; when associated with a-125; a-127 and a-130.
130	no effect on rnf24-binding; when associated with a-125; a-127 and a-128.
132	increases cation channel activity. increases significantly inward and outward currents and does not show channel inactiv
561	constitutively activates channel.
755–757	decreases calcium ion transport.
755–756	increases calcium ion transport.
826–827	decreases calcium ion transport.
889	increases calcium transport. increases calcium ion transport.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-114508	Effects of PIP2 hydrolysis
R-HSA-139853	Elevation of cytosolic Ca2+ levels
R-HSA-3295583	TRP channels
R-HSA-418890	Role of second messengers in netrin-1 signaling

MSigDB gene sets: 232 (showing top): GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_SINGLE_FERTILIZATION, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, chr11q22, GOBP_POSITIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, DARWICHE_PAPILLOMA_PROGRESSION_RISK, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, REACTOME_EFFECTS_OF_PIP2_HYDROLYSIS, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1

GO Biological Process (16): monoatomic cation transport (GO:0006812), positive regulation of cytosolic calcium ion concentration (GO:0007204), single fertilization (GO:0007338), neuron differentiation (GO:0030182), positive regulation of ion transmembrane transporter activity (GO:0032414), positive regulation of neuron differentiation (GO:0045666), negative regulation of dendrite morphogenesis (GO:0050774), regulation of cytosolic calcium ion concentration (GO:0051480), positive regulation of calcium ion transport (GO:0051928), cellular response to hydrogen peroxide (GO:0070301), calcium ion transmembrane transport (GO:0070588), cellular response to hypoxia (GO:0071456), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (11): actin binding (GO:0003779), monoatomic cation channel activity (GO:0005261), calcium channel activity (GO:0005262), store-operated calcium channel activity (GO:0015279), clathrin binding (GO:0030276), protein homodimerization activity (GO:0042803), actinin binding (GO:0042805), ATPase binding (GO:0051117), inositol 1,4,5 trisphosphate binding (GO:0070679), monoatomic ion channel activity (GO:0005216), protein binding (GO:0005515)

GO Cellular Component (5): cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020), cation channel complex (GO:0034703), slit diaphragm (GO:0036057)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
G alpha (q) signalling events	1
Platelet activation, signaling and aggregation	1
Platelet calcium homeostasis	1
Stimuli-sensing channels	1
Netrin-1 signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monoatomic ion transport	2
monoatomic ion transmembrane transporter activity	2
calcium ion transport	2
transport	2
cytoskeletal protein binding	2
cellular anatomical structure	2
regulation of biological quality	1
fertilization	1
cell differentiation	1
generation of neurons	1
regulation of transmembrane transporter activity	1
positive regulation of transporter activity	1
positive regulation of monoatomic ion transmembrane transport	1
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1
negative regulation of cell projection organization	1
dendrite morphogenesis	1
regulation of dendrite morphogenesis	1
negative regulation of neurogenesis	1
intracellular calcium ion homeostasis	1
positive regulation of monoatomic ion transport	1
regulation of calcium ion transport	1
cellular response to reactive oxygen species	1
response to hydrogen peroxide	1
monoatomic cation transmembrane transport	1
response to hypoxia	1
cellular response to stress	1
cellular response to decreased oxygen levels	1
metal ion transport	1
transmembrane transport	1
cellular process	1
monoatomic ion channel activity	1
monoatomic cation transmembrane transporter activity	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
calcium channel activity	1
protein binding	1
identical protein binding	1
protein dimerization activity	1

Protein interactions and networks

STRING

1720 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRPC6	NPHS2	Q9NP85	998
TRPC6	NPHS1	O60500	990
TRPC6	ORAI2	Q96SN7	983
TRPC6	STIM1	Q13586	971
TRPC6	TRPV4	Q9HBA0	941
TRPC6	ACTN4	O43707	904
TRPC6	CD2AP	Q9Y5K6	903
TRPC6	INF2	Q27J81	901
TRPC6	STIM2	Q9P246	885
TRPC6	PLCE1	Q9P212	877
TRPC6	TRPM4	Q8TD43	867
TRPC6	TRPC3	Q13507	866
TRPC6	RNF24	Q9Y225	855
TRPC6	TRPC1	P48995	832
TRPC6	ORAI3	Q9BRQ5	824

IntAct

6 interactions, top by confidence:

A	B	Type	Score
TRPC6	MX1	psi-mi:“MI:0915”(physical association)	0.580
MX1	TRPC6	psi-mi:“MI:0915”(physical association)	0.580
TRPC6	AP2M1	psi-mi:“MI:0407”(direct interaction)	0.440
ITPR3	TRPC6	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (93): FYN (Affinity Capture-Western), TRPC6 (Biochemical Activity), TRPC6 (Affinity Capture-Western), TRPC6 (Reconstituted Complex), TRPC6 (Affinity Capture-Western), TRPC6 (Affinity Capture-Western), TRPC2 (Affinity Capture-Western), TRPC6 (Affinity Capture-Western), TRPC6 (Affinity Capture-Western), TRPC6 (Affinity Capture-Western), TRPC6 (Affinity Capture-Western), TRPC6 (Affinity Capture-Western), TRPC6 (Affinity Capture-Western), TRPC6 (Co-localization), TRPC6 (Co-localization)

ESM2 similar proteins: A1A5B4, A2A259, A2AIR5, E9PTA2, F6RG56, H2Q5A1, O35245, O62826, O70212, O94759, P02715, P04758, P09690, P11230, P13536, P23979, P25109, P35563, P37088, Q04671, Q13507, Q13563, Q4GZT3, Q60HE8, Q6IVV8, Q7Z403, Q86V40, Q8BWC0, Q8MIQ9, Q8R4F0, Q8TCT7, Q8TCU5, Q8TDD5, Q91YD4, Q96BD0, Q99J21, Q9EQJ0, Q9GZU1, Q9HA82, Q9JJH7

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

7 interactions.

A	Effect	B	Mechanism
TRPC6	“up-regulates activity”	PPP3CA
AGT	“up-regulates activity”	TRPC6
TRPC6	“up-regulates quantity”	calcium(2+)	relocalization
SRC	“up-regulates activity”	TRPC6	phosphorylation
FYN	“up-regulates activity”	TRPC6	phosphorylation
PRKG1	“down-regulates activity”	TRPC6	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	23
Uncertain significance	300
Likely benign	106
Benign	52

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1344650	NM_004621.6(TRPC6):c.2684G>T (p.Arg895Leu)	Pathogenic
3598815	NM_004621.6(TRPC6):c.1195C>T (p.Arg399Ter)	Pathogenic
6151	NM_004621.6(TRPC6):c.335C>A (p.Pro112Gln)	Pathogenic
6153	NM_004621.6(TRPC6):c.808T>A (p.Ser270Thr)	Pathogenic
6155	NM_004621.6(TRPC6):c.2683C>T (p.Arg895Cys)	Pathogenic
974548	NM_004621.6(TRPC6):c.2643dup (p.Gly882fs)	Pathogenic
994835	NM_004621.6(TRPC6):c.2605C>T (p.Gln869Ter)	Pathogenic
1712369	NM_004621.6(TRPC6):c.2346dup (p.Trp783fs)	Likely pathogenic
2500623	NM_004621.6(TRPC6):c.325G>A (p.Gly109Ser)	Likely pathogenic
2506480	NM_004621.6(TRPC6):c.2592_2595dup (p.Tyr866fs)	Likely pathogenic
2572471	NM_004621.6(TRPC6):c.2415_2418del (p.Asn805fs)	Likely pathogenic
2585357	NM_004621.6(TRPC6):c.1090dup (p.Ser364fs)	Likely pathogenic
2681752	NM_004621.6(TRPC6):c.1891_1894del (p.Val631fs)	Likely pathogenic
2681753	NM_004621.6(TRPC6):c.991G>A (p.Gly331Arg)	Likely pathogenic
2681754	NM_004621.6(TRPC6):c.430G>C (p.Glu144Gln)	Likely pathogenic
2982301	NM_004621.6(TRPC6):c.329A>G (p.Asn110Ser)	Likely pathogenic
3235004	NM_004621.6(TRPC6):c.368C>G (p.Ser123Ter)	Likely pathogenic
3236154	NM_004621.6(TRPC6):c.2619_2626del (p.Asp873fs)	Likely pathogenic
3377201	NM_004621.6(TRPC6):c.2665del (p.Gln889fs)	Likely pathogenic
3598783	NM_004621.6(TRPC6):c.2578_2581dup (p.Arg861fs)	Likely pathogenic
3598799	NM_004621.6(TRPC6):c.1753_1754del (p.Lys585fs)	Likely pathogenic
3598809	NM_004621.6(TRPC6):c.1540del (p.Trp514fs)	Likely pathogenic
3598821	NM_004621.6(TRPC6):c.946-1G>C	Likely pathogenic
3598839	NM_004621.6(TRPC6):c.129C>A (p.Cys43Ter)	Likely pathogenic
4082534	NM_004621.6(TRPC6):c.1758G>A (p.Trp586Ter)	Likely pathogenic
562370	NM_004621.6(TRPC6):c.2534T>G (p.Leu845Arg)	Likely pathogenic
562442	NM_004621.6(TRPC6):c.2284G>A (p.Val762Ile)	Likely pathogenic
829823	NM_004621.6(TRPC6):c.524G>A (p.Arg175Gln)	Likely pathogenic
974547	NM_004621.6(TRPC6):c.2641G>T (p.Glu881Ter)	Likely pathogenic
988133	NM_004621.6(TRPC6):c.644G>A (p.Arg215Gln)	Likely pathogenic

SpliceAI

2847 predictions. Top by Δscore:

Variant	Effect	Δscore
11:101453104:CCC:C	acceptor_gain	1.0000
11:101453105:CC:C	acceptor_gain	1.0000
11:101453105:CCC:C	acceptor_gain	1.0000
11:101453106:CCT:C	acceptor_gain	1.0000
11:101453107:C:CC	acceptor_gain	1.0000
11:101453107:C:T	acceptor_gain	1.0000
11:101453108:T:C	acceptor_gain	1.0000
11:101453109:T:C	acceptor_gain	1.0000
11:101453109:T:TC	acceptor_gain	1.0000
11:101453116:C:CT	acceptor_gain	1.0000
11:101453117:A:T	acceptor_gain	1.0000
11:101453721:ATTTT:A	acceptor_gain	1.0000
11:101453722:TTTT:T	acceptor_gain	1.0000
11:101453723:TTT:T	acceptor_gain	1.0000
11:101453724:TT:T	acceptor_gain	1.0000
11:101453725:TC:T	acceptor_loss	1.0000
11:101453726:C:CA	acceptor_loss	1.0000
11:101453726:C:CC	acceptor_gain	1.0000
11:101453727:T:A	acceptor_loss	1.0000
11:101455013:CTTA:C	donor_loss	1.0000
11:101455014:TTA:T	donor_loss	1.0000
11:101455015:TA:T	donor_loss	1.0000
11:101472230:A:C	donor_gain	1.0000
11:101472331:CT:C	acceptor_gain	1.0000
11:101472333:C:CC	acceptor_gain	1.0000
11:101473507:A:AC	donor_gain	1.0000
11:101473508:C:CC	donor_gain	1.0000
11:101482951:ATTAC:A	donor_gain	1.0000
11:101488933:ATACC:A	donor_loss	1.0000
11:101488934:TA:T	donor_loss	1.0000

AlphaMissense

6206 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:101453070:A:G	L894P	1.000
11:101453087:C:A	K888N	1.000
11:101453087:C:G	K888N	1.000
11:101471346:A:G	L749P	1.000
11:101471366:C:A	W742C	1.000
11:101471366:C:G	W742C	1.000
11:101471368:A:G	W742R	1.000
11:101471368:A:T	W742R	1.000
11:101472179:A:C	N721K	1.000
11:101472179:A:T	N721K	1.000
11:101472183:A:G	L720P	1.000
11:101472189:A:T	V718D	1.000
11:101472216:C:T	G709E	1.000
11:101472217:C:G	G709R	1.000
11:101472217:C:T	G709R	1.000
11:101472222:A:G	L707P	1.000
11:101472231:C:A	G704V	1.000
11:101472231:C:T	G704D	1.000
11:101472232:C:G	G704R	1.000
11:101472301:C:G	A681P	1.000
11:101472302:C:A	W680C	1.000
11:101472302:C:G	W680C	1.000
11:101472304:A:G	W680R	1.000
11:101472304:A:T	W680R	1.000
11:101472309:A:G	L678P	1.000
11:101472320:A:C	S674R	1.000
11:101472320:A:T	S674R	1.000
11:101472322:T:G	S674R	1.000
11:101473514:G:C	F668L	1.000
11:101473514:G:T	F668L	1.000

dbSNP variants (sampled 300 via entrez): RS1000076920 (11:101498207 T>C,G), RS1000086676 (11:101451463 C>A), RS1000098821 (11:101458723 C>T), RS1000139883 (11:101465766 C>A,T), RS1000195696 (11:101511287 G>A,C), RS1000224260 (11:101463960 T>C), RS1000225807 (11:101519406 C>A,T), RS1000227202 (11:101521399 G>A), RS1000230102 (11:101477731 G>T), RS1000246005 (11:101583316 C>A,T), RS1000264170 (11:101464159 C>A,G), RS1000279279 (11:101559743 C>G), RS1000280348 (11:101517171 G>C), RS1000281087 (11:101533308 G>C), RS1000359940 (11:101483628 T>C,G)

Disease associations

OMIM: gene MIM:603652 | disease phenotypes: MIM:603965

GenCC curated gene-disease

Disease	Classification	Inheritance
focal segmental glomerulosclerosis 2	Strong	Autosomal dominant
familial idiopathic steroid-resistant nephrotic syndrome	Supportive	Autosomal dominant

Mondo (6): focal segmental glomerulosclerosis 2 (MONDO:0011390), nephrotic syndrome (MONDO:0005377), focal segmental glomerulosclerosis (MONDO:0100313), kidney disorder (MONDO:0005240), atypical hemolytic-uremic syndrome (MONDO:0016244), familial idiopathic steroid-resistant nephrotic syndrome (MONDO:0019006)

Orphanet (2): Hereditary steroid-resistant nephrotic syndrome (Orphanet:656), Atypical hemolytic uremic syndrome (Orphanet:2134)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000093	Proteinuria
HP:0000097	Focal segmental glomerulosclerosis
HP:0000100	Nephrotic syndrome
HP:0000707	Abnormality of the nervous system
HP:0000737	Irritability
HP:0000822	Hypertension
HP:0000969	Edema
HP:0001945	Fever
HP:0001967	Diffuse mesangial sclerosis
HP:0002027	Abdominal pain
HP:0002315	Headache
HP:0002586	Peritonitis
HP:0003073	Hypoalbuminemia
HP:0003774	Stage 5 chronic kidney disease
HP:0011462	Young adult onset
HP:0011947	Respiratory tract infection
HP:0012579	Minimal change glomerulonephritis
HP:0012622	Chronic kidney disease
HP:0031504	Foamy urine
HP:0100539	Periorbital edema

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002541_89	Menarche (age at onset)	7.000000e-14
GCST004744_47	Lung adenocarcinoma	9.000000e-06
GCST004790_5	Change in LVEF in response to paclitaxel and trastuzumab in HER2+ breast cancer	8.000000e-06
GCST005929_3	Severity of nausea and vomiting of pregnancy	2.000000e-12
GCST007325_14	General risk tolerance (MTAG)	9.000000e-09
GCST011494_57	Daytime nap	4.000000e-13
GCST012490_638	Femur bone mineral density x serum urate levels interaction	4.000000e-09
GCST90002393_439	Monocyte count	5.000000e-14
GCST90002400_472	Plateletcrit	1.000000e-10
GCST90002407_335	White blood cell count	3.000000e-09
GCST90093092_3	DHEAS levels	3.000000e-06

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0008204	left ventricular diastolic function measurement
EFO:0008347	response to trastuzumab
EFO:0009265	nausea and vomiting of pregnancy severity measurement
EFO:0008579	risk-taking behaviour
EFO:0007828	daytime rest measurement
EFO:0004531	urate measurement
EFO:0005091	monocyte count
EFO:0007985	platelet crit
EFO:0007001	dehydroepiandrosterone sulphate measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D065766	Atypical Hemolytic Uremic Syndrome	C12.050.351.968.419.936.463.500; C12.200.777.419.936.463.500; C12.950.419.936.463.500; C15.378.050.141.610.500; C15.378.140.855.925.500.500; C15.378.243.937.925.500.500
D005923	Glomerulosclerosis, Focal Segmental	C12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640
D007674	Kidney Diseases	C12.050.351.968.419; C12.200.777.419; C12.950.419
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643
C565831	Focal Segmental Glomerulosclerosis 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2417347 (SINGLE PROTEIN), CHEMBL4523662 (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: 3,752 (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
CHEMBL1407943	CLEMIZOLE	2	3,752

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 (22 total), top 22:

Ligand	Action	Affinity	Parameter
AM-1473	Antagonist	9.7	pIC50
GSK2833503A	Channel blocker	8.52	pIC50
GSK2332255B	Antagonist	8.4	pIC50
SAR7334	Channel blocker	8.02	pIC50
BTDM	Inhibition	8.0	pIC50
DS88790512	Inhibition	7.92	pIC50
BI 749327	Antagonist	7.9	pIC50
apecotrep	Inhibition	7.54	pIC50
AM-0883	Agonist	7.3	pEC50
SH045	Channel blocker	7.2	pIC50
larixyl acetate	Inhibition	7.0	pIC50
GSK1702934A	Agonist	6.36	pIC50
GSK417651A	Antagonist	6.36	pIC50
Pyrazolo-pyrimidine 14a [PMID: 29859875]	Inhibition	6.0	pIC50
clemizole	Channel blocker	5.89	pIC50
pyrazolopyrimidine 4n	Activation	5.86	pEC50
Gd3+	Antagonist	5.7	pIC50
SKF96365	Antagonist	5.4	pIC50
norgestimate	Channel blocker	5.28	pIC50
La3+	Channel blocker	5.22	pIC50
amiloride	Antagonist	3.9	pIC50
Cd2+	Antagonist	3.6	pIC50

ChEMBL bioactivities

274 potent at pChembl≥5 of 276 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	IC50	0.1	nM	CHEMBL4764496
9.70	IC50	0.2	nM	CHEMBL4741505
9.66	IC50	0.22	nM	CHEMBL5567030
9.52	IC50	0.3	nM	CHEMBL4752852
9.40	IC50	0.4	nM	CHEMBL4776935
9.40	IC50	0.4	nM	CHEMBL4753871
9.40	IC50	0.4	nM	CHEMBL4746182
8.55	IC50	2.8	nM	CHEMBL5832744
8.52	IC50	3	nM	CHEMBL4129456
8.47	IC50	3.37	nM	CHEMBL5847664
8.47	IC50	3.4	nM	CHEMBL5835028
8.46	IC50	3.44	nM	CHEMBL5884133
8.42	IC50	3.78	nM	CHEMBL5995011
8.40	IC50	4	nM	CHEMBL2418809
8.39	IC50	4.06	nM	CHEMBL5759191
8.28	IC50	5.31	nM	CHEMBL6047787
8.24	IC50	5.8	nM	CHEMBL5532633
8.18	IC50	6.56	nM	CHEMBL6040572
8.15	IC50	7.1	nM	CHEMBL5989633
8.10	IC50	8	nM	CHEMBL4129805
8.10	IC50	7.9	nM	CHEMBL4129809
8.10	IC50	7.97	nM	CHEMBL5774406
8.02	IC50	9.5	nM	CHEMBL4129809
8.02	IC50	9.51	nM	CHEMBL5835965
8.02	IC50	9.51	nM	CHEMBL5892236
8.00	IC50	10	nM	CHEMBL5558723
8.00	IC50	9.93	nM	CHEMBL5792157
7.97	IC50	10.6	nM	CHEMBL5870151
7.97	IC50	10.6	nM	CHEMBL5839618
7.96	IC50	11	nM	CHEMBL4127600
7.94	IC50	11.5	nM	CHEMBL5864721
7.89	IC50	13	nM	CHEMBL5567783
7.86	IC50	13.7	nM	CHEMBL6065445
7.85	IC50	14.1	nM	CHEMBL5794171
7.80	IC50	16	nM	CHEMBL2418811
7.80	IC50	16	nM	CHEMBL2418807
7.79	IC50	16.2	nM	CHEMBL5776256
7.76	IC50	17.4	nM	CHEMBL5754111
7.76	IC50	17.4	nM	CHEMBL5895935
7.75	IC50	17.8	nM	CHEMBL5952105
7.71	IC50	19.3	nM	CHEMBL5832093
7.68	IC50	21	nM	CHEMBL2418811
7.68	IC50	20.7	nM	CHEMBL5887941
7.66	IC50	22	nM	CHEMBL4126041
7.66	IC50	22	nM	CHEMBL6046547
7.60	IC50	25	nM	CHEMBL2418808
7.60	IC50	25.1	nM	CHEMBL5993383
7.57	IC50	27	nM	CHEMBL5962399
7.57	IC50	27	nM	CHEMBL6058637
7.57	IC50	27	nM	CHEMBL5892549

PubChem BioAssay actives

62 with measured affinity, of 86 total; 50 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
(3R,4R)-1-[5,6-difluoro-1-[(5-methyl-2-pyridinyl)methyl]benzimidazol-2-yl]-4-fluoropiperidin-3-amine	1719715: Inhibition of human TRPC6 channel transfected in HEK293 cells assessed as intracellular calcium level by FLIPR assay	ic50	0.0001	uM
(3R,4R)-4-fluoro-1-[6-fluoro-1-[(5-fluoropyrimidin-2-yl)methyl]benzimidazol-2-yl]piperidin-3-amine	1719715: Inhibition of human TRPC6 channel transfected in HEK293 cells assessed as intracellular calcium level by FLIPR assay	ic50	0.0002	uM
4-[[(1R,2S)-2-[(3R)-3-aminopiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzonitrile	2079996: Antagonist activity at TRPC6 (unknown origin) assessed as inhibition of channel activity	ic50	0.0002	uM
(3R)-1-[1-[(5-chloro-2-pyridinyl)methyl]-5-fluorobenzimidazol-2-yl]-4,4-difluoropiperidin-3-amine	1719715: Inhibition of human TRPC6 channel transfected in HEK293 cells assessed as intracellular calcium level by FLIPR assay	ic50	0.0003	uM
(3R,4R)-4-fluoro-1-[5-fluoro-1-[(5-fluoropyrimidin-2-yl)methyl]benzimidazol-2-yl]piperidin-3-amine	1719715: Inhibition of human TRPC6 channel transfected in HEK293 cells assessed as intracellular calcium level by FLIPR assay	ic50	0.0004	uM
(3R,4R)-4-fluoro-1-[6-fluoro-1-[(5-fluoro-2-pyridinyl)methyl]benzimidazol-2-yl]piperidin-3-amine	1719715: Inhibition of human TRPC6 channel transfected in HEK293 cells assessed as intracellular calcium level by FLIPR assay	ic50	0.0004	uM
(3R,4R)-1-[1-[(5-chloropyrimidin-2-yl)methyl]-4-fluoro-6-methoxybenzimidazol-2-yl]-4-fluoropiperidin-3-amine	1719715: Inhibition of human TRPC6 channel transfected in HEK293 cells assessed as intracellular calcium level by FLIPR assay	ic50	0.0004	uM
4-[[(1R,2R,3aR,7aS)-2-[(3R)-3-aminopiperidin-1-yl]-5-fluoro-7a-methyl-1,2,3,3a,6,7-hexahydroinden-1-yl]oxy]benzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.0030	uM
[5-chloro-2-[(6-fluoro-1,3-benzodioxol-5-yl)amino]-1,3-thiazol-4-yl]-(2,3-dimethylpiperidin-1-yl)methanone	2079996: Antagonist activity at TRPC6 (unknown origin) assessed as inhibition of channel activity	ic50	0.0040	uM
[(1S,4S,4aR,8aS)-4-[(3S)-3-hydroxy-3-methylpent-4-enyl]-4a,8,8-trimethyl-3-methylidene-2,4,5,6,7,8a-hexahydro-1H-naphthalen-1-yl] N-methylcarbamate	2079996: Antagonist activity at TRPC6 (unknown origin) assessed as inhibition of channel activity	ic50	0.0058	uM
4-[[(1R,2R)-2-[(3R)-3-aminopiperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-chlorobenzonitrile	1578753: Inhibition of human TRPC6 expressed in HEK293 cells assessed as reduction in TRPC6-induced current by Whole-cell patch-clamp	ic50	0.0079	uM
4-[[(1S,2R,3R,4R,6R,7S)-4-[(3R)-3-aminopiperidin-1-yl]-9-oxo-3-tricyclo[5.2.1.02,6]decanyl]oxy]benzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.0080	uM
[2-(1,3-benzodioxol-5-ylamino)-1,3-thiazol-4-yl]-(3,5-dimethylpiperidin-1-yl)methanone	2079996: Antagonist activity at TRPC6 (unknown origin) assessed as inhibition of channel activity	ic50	0.0100	uM
4-[[(1R,2R,3aR,7aS)-2-[(3R)-3-aminopiperidin-1-yl]-7a-methyl-5-oxo-2,3,3a,4,6,7-hexahydro-1H-inden-1-yl]oxy]benzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.0110	uM
[4-(6-aminopyridazin-3-yl)piperidin-1-yl]-[4-(4-tert-butylphenoxy)phenyl]methanone	2079996: Antagonist activity at TRPC6 (unknown origin) assessed as inhibition of channel activity	ic50	0.0130	uM
[2-(1,3-benzodioxol-5-ylamino)-1,3-thiazol-4-yl]-(2,3-dimethylpiperidin-1-yl)methanone	765922: Inhibition of human recombinant TRPC6 expressed in HEK293-MSRII cells assessed as carbachol-stimulated Ca2+/Na+ influx after 10 mins by FLIPR assay	ic50	0.0160	uM
[2-(4-chloro-2-fluoroanilino)-5-methyl-1,3-thiazol-4-yl]-[(2S,3S)-2,3-dimethylpiperidin-1-yl]methanone	765922: Inhibition of human recombinant TRPC6 expressed in HEK293-MSRII cells assessed as carbachol-stimulated Ca2+/Na+ influx after 10 mins by FLIPR assay	ic50	0.0160	uM
4-[[(1R,2R,3aR,6aR)-2-[(3R)-3-aminopiperidin-1-yl]-4-oxo-2,3,3a,5,6,6a-hexahydro-1H-pentalen-1-yl]oxy]benzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.0220	uM
(2,3-dimethylpiperidin-1-yl)-[2-[(6-fluoro-1,3-benzodioxol-5-yl)amino]-5-methyl-1,3-thiazol-4-yl]methanone	765922: Inhibition of human recombinant TRPC6 expressed in HEK293-MSRII cells assessed as carbachol-stimulated Ca2+/Na+ influx after 10 mins by FLIPR assay	ic50	0.0250	uM
4-[[(1R,2R,3aR,7aS)-2-[(3R)-3-aminopiperidin-1-yl]-5,5-difluoro-7a-methyl-2,3,3a,4,6,7-hexahydro-1H-inden-1-yl]oxy]benzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.0300	uM
[2-(1,3-benzodioxol-5-ylamino)-5-methyl-1,3-thiazol-4-yl]-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)methanone	765922: Inhibition of human recombinant TRPC6 expressed in HEK293-MSRII cells assessed as carbachol-stimulated Ca2+/Na+ influx after 10 mins by FLIPR assay	ic50	0.0320	uM
4-[[(1R,2R,3aR,5E,7aS)-2-[(3R)-3-aminopiperidin-1-yl]-5-methoxyimino-7a-methyl-2,3,3a,4,6,7-hexahydro-1H-inden-1-yl]oxy]benzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.0330	uM
4-[[(1R,2R,3aS,7aS)-2-[(3R)-3-aminopiperidin-1-yl]-7a-methyl-1,2,3,3a,4,5,6,7-octahydroinden-1-yl]oxy]benzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.0370	uM
4-[[(1R,2R,3aR,5R,7aS)-2-[(3R)-3-aminopiperidin-1-yl]-5-hydroxy-7a-methyl-1,2,3,3a,4,5,6,7-octahydroinden-1-yl]oxy]benzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.0490	uM
[2-(4-chloro-2-fluoroanilino)-5-methyl-1,3-thiazol-4-yl]-(2,3-dimethylpiperidin-1-yl)methanone	765922: Inhibition of human recombinant TRPC6 expressed in HEK293-MSRII cells assessed as carbachol-stimulated Ca2+/Na+ influx after 10 mins by FLIPR assay	ic50	0.0500	uM
4-[[(1R,2R,3aR,5R,7aS)-2-[(3R)-3-aminopiperidin-1-yl]-5-methoxy-7a-methyl-1,2,3,3a,4,5,6,7-octahydroinden-1-yl]oxy]benzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.0520	uM
[2-(1,3-benzodioxol-5-ylamino)-1,3-thiazol-4-yl]-(1-methyl-3,4-dihydro-1H-isoquinolin-2-yl)methanone	765922: Inhibition of human recombinant TRPC6 expressed in HEK293-MSRII cells assessed as carbachol-stimulated Ca2+/Na+ influx after 10 mins by FLIPR assay	ic50	0.0630	uM
(2,3-dimethylpiperidin-1-yl)-[2-(4-methylanilino)-1,3-thiazol-4-yl]methanone	765922: Inhibition of human recombinant TRPC6 expressed in HEK293-MSRII cells assessed as carbachol-stimulated Ca2+/Na+ influx after 10 mins by FLIPR assay	ic50	0.0800	uM
4-[[(1R,2R,3R,5R)-3-[(3R)-3-aminopiperidin-1-yl]-6-oxo-2-bicyclo[3.2.0]heptanyl]oxy]benzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.1600	uM
[2-(1,3-benzodioxol-5-ylamino)-1,3-thiazol-4-yl]-(3,4-dihydro-1H-isoquinolin-2-yl)methanone	765922: Inhibition of human recombinant TRPC6 expressed in HEK293-MSRII cells assessed as carbachol-stimulated Ca2+/Na+ influx after 10 mins by FLIPR assay	ic50	0.1600	uM
[2-(1,3-benzodioxol-5-ylamino)-1,3-thiazol-4-yl]-(4-methylpiperidin-1-yl)methanone	765922: Inhibition of human recombinant TRPC6 expressed in HEK293-MSRII cells assessed as carbachol-stimulated Ca2+/Na+ influx after 10 mins by FLIPR assay	ic50	0.1600	uM
[(1S,4S,4aR,8aS)-4-[(3R)-3-hydroxy-3-methylpent-4-enyl]-4a,8,8-trimethyl-3-methylidene-2,4,5,6,7,8a-hexahydro-1H-naphthalen-1-yl] carbamate	1578747: Inhibition of human TRPC6 expressed in HEK293 cells assessed as reduction in OAG-induced calcium influx preincubated for 2 mins followed by OAG stimulation by fluo-4/AM dye based FLIPR assay	ic50	0.1700	uM
4-[[(1R,2R,3aS,5S,7aS)-2-[(3R)-3-aminopiperidin-1-yl]-5-(difluoromethyl)-7a-methyl-1,2,3,3a,4,5,6,7-octahydroinden-1-yl]oxy]benzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.2000	uM
4-[[(1R,2R,3aR,7aS)-2-[(3R)-3-aminopiperidin-1-yl]-5-hydroxy-5,7a-dimethyl-2,3,3a,4,6,7-hexahydro-1H-inden-1-yl]oxy]benzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.2100	uM
[(3R)-5-[(1S,4S,4aS,8aR)-4-carbamoyloxy-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl]-3-methylpent-1-en-3-yl] acetate	1578747: Inhibition of human TRPC6 expressed in HEK293 cells assessed as reduction in OAG-induced calcium influx preincubated for 2 mins followed by OAG stimulation by fluo-4/AM dye based FLIPR assay	ic50	0.2500	uM
(2E)-2-[(1R,2R,3aS,7aS)-2-[(3R)-3-aminopiperidin-1-yl]-1-(4-cyanophenoxy)-7a-methyl-2,3,3a,4,6,7-hexahydro-1H-inden-5-ylidene]-N,N-dimethylacetamide	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.2800	uM
4-[[(1R,2R,3aS,7aR)-2-[(3R)-3-aminopiperidin-1-yl]-7a-methyl-5-oxo-2,3,3a,4,6,7-hexahydro-1H-inden-1-yl]oxy]benzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.3900	uM
[2-(4-methylanilino)-1,3-thiazol-4-yl]-(4-methylpiperidin-1-yl)methanone	765922: Inhibition of human recombinant TRPC6 expressed in HEK293-MSRII cells assessed as carbachol-stimulated Ca2+/Na+ influx after 10 mins by FLIPR assay	ic50	0.4000	uM
4-[[(1R,2R,3aR,5S,7aS)-2-[(3R)-3-aminopiperidin-1-yl]-5-methoxy-7a-methyl-1,2,3,3a,4,5,6,7-octahydroinden-1-yl]oxy]benzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.4400	uM
3,4-dihydro-1H-isoquinolin-2-yl-[2-(4-methoxyanilino)-1,3-thiazol-4-yl]methanone	765922: Inhibition of human recombinant TRPC6 expressed in HEK293-MSRII cells assessed as carbachol-stimulated Ca2+/Na+ influx after 10 mins by FLIPR assay	ic50	0.5000	uM
4-[(1R,2R)-2-[(3R)-3-aminopiperidin-1-yl]cyclopentyl]oxybenzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.5000	uM
4-[[(1R,2R,3aR,5S,7aS)-2-[(3R)-3-aminopiperidin-1-yl]-5-hydroxy-7a-methyl-1,2,3,3a,4,5,6,7-octahydroinden-1-yl]oxy]benzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.5600	uM
[2-(4-chloro-2-fluoroanilino)-1,3-thiazol-4-yl]-(4-methylpiperidin-1-yl)methanone	765922: Inhibition of human recombinant TRPC6 expressed in HEK293-MSRII cells assessed as carbachol-stimulated Ca2+/Na+ influx after 10 mins by FLIPR assay	ic50	0.6300	uM
[2-(4-methylanilino)-1,3-thiazol-4-yl]-(2-methylpiperidin-1-yl)methanone	765922: Inhibition of human recombinant TRPC6 expressed in HEK293-MSRII cells assessed as carbachol-stimulated Ca2+/Na+ influx after 10 mins by FLIPR assay	ic50	0.6300	uM
4-[(1R,2R)-2-[(3R)-3-aminopiperidin-1-yl]cyclopentyl]oxy-3-chlorobenzonitrile	1496089: Inhibition of human TRPC6 expressed in HEK293 cells assessed as decrease in intracellular calcium level after 24 hrs by Fluo-4 dye-based FLIPR assay	ic50	0.6600	uM
[2-(4-methoxyanilino)-1,3-thiazol-4-yl]-(4-methylpiperidin-1-yl)methanone	765922: Inhibition of human recombinant TRPC6 expressed in HEK293-MSRII cells assessed as carbachol-stimulated Ca2+/Na+ influx after 10 mins by FLIPR assay	ic50	0.8000	uM
[2-(4-chloroanilino)-1,3-thiazol-4-yl]-(4-methylpiperidin-1-yl)methanone	765922: Inhibition of human recombinant TRPC6 expressed in HEK293-MSRII cells assessed as carbachol-stimulated Ca2+/Na+ influx after 10 mins by FLIPR assay	ic50	0.8000	uM
ethyl 4-[3-(4-fluorophenyl)-7-hydroxy-2-methyl-3,5-dihydropyrazolo[1,5-a]pyrimidin-5-yl]-4-methylpiperidine-1-carboxylate	2079996: Antagonist activity at TRPC6 (unknown origin) assessed as inhibition of channel activity	ic50	1.0000	uM
[2-(1,3-benzodioxol-5-ylamino)-5-methyl-1,3-thiazol-4-yl]-(5-methyl-7,8-dihydro-5H-1,6-naphthyridin-6-yl)methanone	765922: Inhibition of human recombinant TRPC6 expressed in HEK293-MSRII cells assessed as carbachol-stimulated Ca2+/Na+ influx after 10 mins by FLIPR assay	ic50	1.2600	uM
(1S,4S,4aR,8aS)-4-[(3R)-3-hydroxy-3-methylpent-4-enyl]-4a,8,8-trimethyl-3-methylidene-2,4,5,6,7,8a-hexahydro-1H-naphthalen-1-ol	1578746: Inhibition of human TRPC6 expressed in thapsigargin pretreated HEK293 cells assessed as reduction in GPCR-induced calcium entry by fluo-4/AM dye based assay	ic50	1.5700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, decreases expression	3
Calcium	increases uptake, increases abundance, increases activity, affects transport, increases reaction	3
Estradiol	affects cotreatment, decreases expression, increases expression	3
trichostatin A	affects expression, decreases reaction, increases expression	2
entinostat	increases expression, affects cotreatment	2
bisphenol S	decreases expression, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Flufenamic Acid	increases activity, increases uptake	2
Aflatoxin B1	increases expression, decreases methylation	2
geldanamycin	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
diphenyleneiodonium	decreases reaction, increases expression	1
8-bromocyclic GMP	increases phosphorylation, decreases reaction	1
sodium arsenite	decreases expression	1
2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone	decreases activity	1
fasudil	decreases reaction, increases expression	1
di-n-butylphosphoric acid	affects expression	1
KT 5823	decreases reaction, increases phosphorylation	1
manganese(III)-tetrakis(4-benzoic acid)porphyrin	decreases reaction, increases expression	1
Y 27632	decreases reaction, increases expression	1
4-((3,4-(methylenedioxy)benzyl)amino)-6-methoxyquinazoline	increases phosphorylation, decreases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Catechin	affects cotreatment, increases expression	1

ChEMBL screening assays

30 unique, capped per target: 30 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2422302	Binding	Inhibition of human recombinant TRPC6 expressed in HEK293 cells assessed as 1-oleoyl-2-acetyl-glycerol-stimulated current at 0.01 to 0.03 uM by whole cell electrophysiology assay	The discovery of potent blockers of the canonical transient receptor channels, TRPC3 and TRPC6, based on an anilino-thiazole pharmacophore. — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_5I81	ValiScreen human TRPC6	Transformed cell line	Female
CVCL_C6SR	BCRTi006-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00308321	PHASE4	UNKNOWN	Long Term Tapering or Standard Steroids for Nephrotic Syndrome
NCT01021540	PHASE4	COMPLETED	Prospective Study Evaluating the Effect of Repository Corticotropin in the Treatment of Various Nephrotic Syndromes
NCT01028287	PHASE4	COMPLETED	Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN)
NCT01162005	PHASE4	COMPLETED	Therapeutic Effect of Tacrolimus on Primary Nephrotic Syndrome in Children
NCT01895894	PHASE4	COMPLETED	Mycophenolate Mofetil in Pediatric Steroid Dependent Nephrotic Syndrome
NCT02238418	PHASE4	COMPLETED	Efficacy of Usual Vitamin D Supplementation and Its Impact on Children and Adolescents Calciuria.
NCT02382575	PHASE4	UNKNOWN	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Resistant Nephrotic Syndrome
NCT02427880	PHASE4	COMPLETED	Role of Acetazolamide and Hydrochlorothiazide Followed by Furosemide in Treating Nephrotic Edema
NCT03210688	PHASE4	COMPLETED	Active Vitamin D And Reduced Dose Prednisolone for Treatment in Minimal Change Nephropathy
NCT03347357	PHASE4	COMPLETED	Pharmacokinetics of Tacrolimus in Children
NCT05696977	PHASE4	UNKNOWN	Effect of Obesity on Cyclosporine Blood Trough Level in Nephrotic Syndrome Patients
NCT05966818	PHASE4	UNKNOWN	Effect of Dapagliflozin in Non-Diabetic Patients With Nephrotic Syndrome.
NCT06026787	PHASE4	COMPLETED	Clinical Value of Adding Dapagliflozin in Patients With Nephrotic Syndrome
NCT01129557	PHASE4	TERMINATED	Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease
NCT02399462	PHASE4	WITHDRAWN	Acthar for Treatment of Post-transplant FSGS
NCT02585804	PHASE4	COMPLETED	Treating to Reduce Albuminuria and Normalize Hemodynamic Function in Focal ScLerosis With dApagliflozin Trial Effects
NCT02633046	PHASE4	COMPLETED	Acthar for Treatment-Resistant or Treatment-Intolerant Proteinuria
NCT07219121	PHASE4	RECRUITING	Sparsentan in Posttransplant Immunoglobulin A Nephropathy or Focal Segmental Glomerulosclerosis
NCT00067990	PHASE4	COMPLETED	Angiotensin II Blockade for Chronic Allograft Nephropathy
NCT00117078	PHASE4	COMPLETED	Aranesp® Monthly Preference Study - 2
NCT00117130	PHASE4	COMPLETED	Study to Evaluate Effectiveness of Aranesp®
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00140985	PHASE4	COMPLETED	Antiproteinuric Efficacy of Losartan Potassium in Patients With Non-Diabetic Proteinuric Renal Diseases (0954-213)
NCT00246129	PHASE4	COMPLETED	CamTac Trial:Campath-Tacrolimus vs IL2R MoAb/Tacrolimus/MMF in Renal Transplantation
NCT00275535	PHASE4	COMPLETED	The Comparison of Tacrolimus and Sirolimus Immunosuppression Based Drug Regimens in Kidney Transplant Recipients
NCT00282217	PHASE4	COMPLETED	Study Evaluating Sirolimus in the Treatment of Kidney Transplant
NCT00289614	PHASE4	COMPLETED	Patients With Renal Impairment and Diabetes Undergoing Computed Tomography (CT)
NCT00290069	PHASE4	UNKNOWN	Renal Function Optimization With Mycophenolate Mofetil (MMF) Immunosuppressor Regimes (ALHAMBRA)
NCT00338468	PHASE4	TERMINATED	A Study to Assess Disability in Anemic Elderly Patients With Kidney Disease Receiving PROCRIT (Epoetin Alfa)
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00443508	PHASE4	UNKNOWN	Reduction or Discontinuation of CNI’s With Conversion to Everolimus-Based Immunosuppresion
NCT00452478	PHASE4	TERMINATED	Conversion From Standard Phosphate Binder Therapy to Fosrenol® (Lanthanum Carbonate) in Chronic Kidney Disease Stage 5
NCT00492518	PHASE4	COMPLETED	Acetylcysteine, Theophylline, and a Combination of Both in the Prophylaxis of Contrast-Induced Nephropathy
NCT00505102	PHASE4	UNKNOWN	Safe Renal Function In Long Term Heart Transplanted Patients
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00688480	PHASE4	COMPLETED	Do Xanthine Oxidase Inhibitors Reduce Both Left Ventricular Hypertrophy and Endothelial Dysfunction in Cardiovascular Patients With Renal Dysfunction?
NCT00863707	PHASE4	COMPLETED	A Study of the Safety and Tolerance of Regadenoson in Subjects With Renal Impairment