TRPC5

Summary

TRPC5 (transient receptor potential cation channel subfamily C member 5, HGNC:12337) is a protein-coding gene on chromosome Xq23, encoding Short transient receptor potential channel 5 (Q9UL62). Forms a receptor-activated non-selective calcium permeant cation channel.

This gene belongs to the transient receptor family. It encodes one of the seven mammalian TRPC (transient receptor potential channel) proteins. The encoded protein is a multi-pass membrane protein and is thought to form a receptor-activated non-selective calcium permeant cation channel. The protein is active alone or as a heteromultimeric assembly with TRPC1, TRPC3, and TRPC4. It also interacts with multiple proteins including calmodulin, CABP1, enkurin, Na(+)-H+ exchange regulatory factor (NHERF ), interferon-induced GTP-binding protein (MX1), ring finger protein 24 (RNF24), and SEC14 domain and spectrin repeat-containing protein 1 (SESTD1).

Source: NCBI Gene 7224 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Moderate, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 295 total
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_012471

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12337
Approved symbol	TRPC5
Name	transient receptor potential cation channel subfamily C member 5
Location	Xq23
Locus type	gene with protein product
Status	Approved
Aliases	PPP1R159
Ensembl gene	ENSG00000072315
Ensembl biotype	protein_coding
OMIM	300334
Entrez	7224

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000262839

RefSeq mRNA: 1 — MANE Select: NM_012471 NM_012471

CCDS: CCDS14561

Canonical transcript exons

ENST00000262839 — 11 exons

Exon	Start	End
ENSE00000393975	111853770	111854106
ENSE00000552664	111912291	111912812
ENSE00000674626	111852298	111852437
ENSE00000674628	111847114	111847436
ENSE00000674630	111834921	111835116
ENSE00000674632	111781935	111782138
ENSE00000674635	111781165	111781206
ENSE00000674645	111778985	111779074
ENSE00001153176	111952043	111952441
ENSE00001213684	112081879	112082776
ENSE00001213695	111768011	111777002

Expression profiles

Bgee: expression breadth broad, 37 present calls, max score 72.12.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2586 / max 18.3589, expressed in 93 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200195	0.2105	85
200196	0.0481	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	72.12	gold quality
cortical plate	UBERON:0005343	71.45	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	64.83	gold quality
prefrontal cortex	UBERON:0000451	62.71	gold quality
frontal cortex	UBERON:0001870	52.84	gold quality
mucosa of stomach	UBERON:0001199	51.54	gold quality
neocortex	UBERON:0001950	51.17	gold quality
bone marrow cell	CL:0002092	50.29	gold quality
ganglionic eminence	UBERON:0004023	49.70	gold quality
liver	UBERON:0002107	48.95	gold quality
Brodmann (1909) area 9	UBERON:0013540	48.07	gold quality
cerebral cortex	UBERON:0000956	47.43	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	46.83	gold quality
primary visual cortex	UBERON:0002436	46.59	gold quality
hypothalamus	UBERON:0001898	46.58	gold quality
right lobe of liver	UBERON:0001114	46.11	gold quality
colonic epithelium	UBERON:0000397	45.41	gold quality
anterior cingulate cortex	UBERON:0009835	45.28	gold quality
upper leg skin	UBERON:0004262	45.15	silver quality
occipital lobe	UBERON:0002021	44.87	gold quality
right frontal lobe	UBERON:0002810	43.89	gold quality
calcaneal tendon	UBERON:0003701	43.79	gold quality
superior frontal gyrus	UBERON:0002661	43.68	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
corpus callosum	UBERON:0002336	43.30	silver quality
secondary oocyte	CL:0000655	42.57	gold quality
tendon	UBERON:0000043	42.32	gold quality
forebrain	UBERON:0001890	42.01	gold quality
brain	UBERON:0000955	41.74	gold quality
bone marrow	UBERON:0002371	41.56	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.90
E-ENAD-17	no	17.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

178 targeting TRPC5, 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-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 40)

• a strong functional link between the operation of expressed TRPC channels and endogenous SOC activity. (PMID:15647288)
• TRPC1 and/or TRPC5 channels serve as store-operated Ca2+ channels in A431 cells, and may function as regulators for intracellular Ca2+ signaling. (PMID:15763245)
• findings suggest intracellular Ca(2+)-calmodulin activates myosin light chain kinase thereby maintaining TRPC5 activity by promotion of membrane TRPC5 distribution under control of phosphorylation/dephosphorylation equilibrium of myoisin light chain (PMID:16284075)
• TRPC5 calcium channel has a lysophospholipid-sensing capability that confers the property of a lipid ionotropic receptor (PMID:16368680)
• TRPC-derived pool of calcium contributes to selective activation of calcineurin in diseased heart (PMID:16950785)
• TRPC5 is a broadly expressed calcium channel with capability to act as an integrator of extracellular and intracellular signals at the level of calcium entry–{REVIEW} (PMID:17217053)
• TRPC5 calcium channel has a role in bipolar phospholipid sensing [review] (PMID:17233612)
• TRPC5 is potentiated by protons and may act as a sensor of pH that links decreases in extracellular pH to Ca(2+) entry and depolarization (PMID:17884814)
• activity of TRPC5 channels may be linked to cellular metabolism via changes in ATP levels and could be involved in Ca(2+) overload occurring after ischemia when ATP is depleted (PMID:17925457)
• conclusion, TRPC5 is a molecular candidate for NSCC activated by muscarinic receptor stimulation. (PMID:17981154)
• TRPC5 and TRPC1 are expressed in secretory fibroblast-like synoviocytes from patients with rheumatoid arthritis, and endogenous TRPC5-TRPC1 channels of the cells are activated by reduced thioredoxin (PMID:18172497)
• analysis of a TRPC6-TRPC5 channel cascade that restricts endothelial cell movement (PMID:18495872)
• Results indicate complex functions for regulation of TRPC5 by PIP2, and suggest that membrane polyphosphoinositides may have at least two distinct functions in regulating TRPC5 channel activity. (PMID:18665391)
• TRPC5 forms Ca(2+)-activated cation channels that are functionally coupled to Ca(2+)-selective ion channels through local Ca(2+) increases beneath the plasma membrane (PMID:19815560)
• 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)
• Stimulation of calcium-permeable TRPC5-containing channels may be an early event in cellular responses to oxidized phospholipids that couples to cell migration and requires an unidentified G protein-coupled receptor. (PMID:20378846)
• Nitric oxide donors fail to modulate activity of human TRPC5 channels exogenously expressed in HEK293 cells. (PMID:20390293)
• TRPC5 channel sensitivities to antioxidants and hydroxylated stilbenes. (PMID:21127073)
• This study demonstrated a new mechanism of TRPC5 regulation via a cAMP signaling via Galpha(s) and protein kinase A. (PMID:21734191)
• TRPC5 and TRPC6 channels are known as the Ca(2+) influx pathways for a previously described, nonselective, cationic current in podocytes. (PMID:21980113)
• findings demonstrate that highly cold-sensitive TRPC5 channels are a molecular component for detection and regional adaptation to cold temperatures in the peripheral nervous system that is distinct from noxious cold sensing (PMID:22025699)
• 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)
• these results suggest that the Galpha(s)-cAMP pathway potentiates the activity of TRPC5 via facilitating intracellular Ca(2+) dynamics and increasing channel trafficking to the plasma membrane. (PMID:22490661)
• Adipocyte TRPC1 and TRPC5 contribute a constitutively active heteromultimeric channel that negatively regulates adiponectin, and through which the omega-3 fatty acids enhance adiponectin’s anti-inflammatory activities. (PMID:22668831)
• Transient receptor potential channel TRPC5 is essential for P-glycoprotein induction in drug-resistant cancer cells. (PMID:22988121)
• Data using recombinant proteins expressed in vascular endothelial cells suggest that SigmaR1 (sigma 1-type opioid receptor) is not involved in regulation of calcium signaling via TRPC5/TRPM3 (transient receptor potential cation channels C5/M3). (PMID:23121507)
• 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)
• Riluzole can activate TRPC5 heterologously expressed in HEK293 cells as well as those endogenously expressed in the U-87 glioblastoma cell line. (PMID:24117252)
• these results suggest that hypoosmotic cell-swelling activates Gq-coupled receptors, which in turn enhance the activation of TRPC5 by regulating this channel membrane trafficking (PMID:24177920)
• Microvesicles from tumor cells transferred TrpC5 to endothelial cells, inducing the expression of P-glycoprotein by activation of the transcription factor NFATc3 (nuclear factor of activated T cells isoform c3). (PMID:24582564)
• TrpC5-containing circulating extracellular vesicles may transfer chemoresistance. (PMID:24733904)
• TRPC5 mRNA and protein levels were up-regulated in focal cortical dysplasia cortical lesions. (PMID:25085710)
• Clemizole exhibits a sixfold selectivity for TRPC5. (PMID:25140002)
• Suppressing TrpC5 expression decreased nuclear beta-catenin accumulation, reduced the induction of ABCB1, and reversed 5-fluorouracil neoplastic resistance. (PMID:25404731)
• TrpC5 plays an important role in VEGF-mediated tumor angiogenesis, suggesting its potential clinical value for anti-angiogenesis therapy (PMID:25579062)
• Transient receptor potential canonical 5 (TRPC5) protects against pain and vascular inflammation in arthritis and joint inflammation. (PMID:27165180)
• TrpC5 causes a robust rise in [Ca2+]i, enhanced Wnt5a expression and nuclear translocation of beta-catenin, leading to reduced differentiation and enhanced cancer cell stemness. (PMID:27895148)
• that Arg-593, a residue located in the E4 loop near the TRPC5 extracellular Gd(3+) binding site, is critical for conferring the sensitivity to GPCR-Gq/11-PLC-dependent gating on TRPC5. (PMID:27920205)
• The essential role of TrpC5 in GLUT1 induction and chemoresistance in colorectal cancer. (PMID:28000878)
• circulating exosome-carrying TRPC5 might act as a noninvasive chemoresistance marker and might serve as an adjuvant to the current imaging examination-based chemoresistance. (PMID:28032400)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	trpc5b	ENSDARG00000060837
danio_rerio	trpc5a	ENSDARG00000070504
mus_musculus	Trpc5	ENSMUSG00000041710
rattus_norvegicus	Trpc5	ENSRNOG00000027233
drosophila_melanogaster	trp	FBGN0003861
drosophila_melanogaster	trpl	FBGN0005614
drosophila_melanogaster	Trpgamma	FBGN0032593
caenorhabditis_elegans		WBGENE00006615

Paralogs (5): TRPC7 (ENSG00000069018), TRPC4 (ENSG00000133107), TRPC6 (ENSG00000137672), TRPC3 (ENSG00000138741), TRPC1 (ENSG00000144935)

Protein

Protein identifiers

Short transient receptor potential channel 5 — Q9UL62 (reviewed: Q9UL62)

Alternative names: Transient receptor protein 5

All UniProt accessions (1): Q9UL62

UniProt curated annotations — full annotation on UniProt →

Function. Forms a receptor-activated non-selective calcium permeant cation channel. Mediates calcium-dependent phosphatidylserine externalization and apoptosis in neurons via its association with PLSCR1. Acts on distinct neuronal populations in the hypothalamus to regulate innate behaviors including feeding, anxiety (flight/fight/fear), socialization, and maternal care.

Subunit / interactions. Homotetramer. Heterotetramer with TRPC1 and/or TRPC4. Each subunit in the homomeric ion channel (via ANK repeats) interacts with one copy of GTP-bound GNAI3; the interaction is direct and activates the ion channel. Interacts with TRPC4AP. Interacts with NHERF1. Interacts with MX1 and RNF24. Interacts (via C-terminus) with CABP1. Interacts with SESTD1 (via the spectrin 1 repeat). Interacts with PLSCR1. Interacts with PKD2L2.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in brain with higher levels in fetal brain. Found in cerebellum and occipital pole.

Disease relevance. Loss-of-function variants in TRPC5 may be involved in a mental disorder characterized by maladaptive behavior, anxiety, autism, postpartum depression, extreme food-seeking and hoarding behavior, hyperphagia and obesity.

Activity regulation. Activated by G-protein coupled receptors via direct interaction with GTP-bound GNAI3, which increases the channel sensitivity to phosphatidylinositol bisphosphate. May be activated by intracellular calcium store depletion. Calcium channel activity is enhanced by MYLK, that promotes its subcellular localization at the plasma membrane.

Similarity. Belongs to the transient receptor (TC 1.A.4) family. STrpC subfamily. TRPC5 sub-subfamily.

RefSeq proteins (1): NP_036603* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR002153	TRPC_channel	Family
IPR005461	TRPC5_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), 1 shown:

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

UniProt features (94 total): helix 37, strand 10, sequence variant 9, topological domain 8, binding site 8, transmembrane region 6, turn 5, repeat 4, region of interest 3, chain 1, intramembrane region 1, glycosylation site 1, disulfide bond 1

Structure

Experimental structures (PDB)

30 structures.

PDB	Method	Resolution (Å)
9RRF	ELECTRON MICROSCOPY	2.3
9GKB	ELECTRON MICROSCOPY	2.32
7WDB	ELECTRON MICROSCOPY	2.4
9LZY	ELECTRON MICROSCOPY	2.43
9M36	ELECTRON MICROSCOPY	2.48
9RRM	ELECTRON MICROSCOPY	2.5
9RRN	ELECTRON MICROSCOPY	2.5
9M5V	ELECTRON MICROSCOPY	2.53
9G4Y	ELECTRON MICROSCOPY	2.6
9GL6	ELECTRON MICROSCOPY	2.6
9M4W	ELECTRON MICROSCOPY	2.62
9KHJ	ELECTRON MICROSCOPY	2.62
7D4P	ELECTRON MICROSCOPY	2.7
9KHI	ELECTRON MICROSCOPY	2.7
7D4Q	ELECTRON MICROSCOPY	2.74
9RRO	ELECTRON MICROSCOPY	2.8
9G50	ELECTRON MICROSCOPY	2.9
9KHK	ELECTRON MICROSCOPY	2.9
9RRQ	ELECTRON MICROSCOPY	2.9
6YSN	ELECTRON MICROSCOPY	3
7E4T	ELECTRON MICROSCOPY	3
9RSH	ELECTRON MICROSCOPY	3
9RVV	ELECTRON MICROSCOPY	3
9LZZ	ELECTRON MICROSCOPY	3.03
7X6C	ELECTRON MICROSCOPY	3.15
9RRU	ELECTRON MICROSCOPY	3.2
9RSG	ELECTRON MICROSCOPY	3.2
8GVW	ELECTRON MICROSCOPY	3.59
8GVX	ELECTRON MICROSCOPY	3.91
7X6I	ELECTRON MICROSCOPY	3.93

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UL62-F1	73.82	0.37

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; 418; 421; 436; 439

Disulfide bonds (1): 553–558

Glycosylation sites (1): 461

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: 244 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_REGULATION_OF_DENDRITE_MORPHOGENESIS, GOBP_GROWTH, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_NEUROGENESIS, GOBP_NEGATIVE_REGULATION_OF_DENDRITE_MORPHOGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GGGTGGRR_PAX4_03, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_MEMBRANE_LIPID_DISTRIBUTION

GO Biological Process (16): calcium ion transport (GO:0006816), positive regulation of cytosolic calcium ion concentration (GO:0007204), nervous system development (GO:0007399), positive regulation of cell population proliferation (GO:0008284), neuron differentiation (GO:0030182), positive regulation of neuron differentiation (GO:0045666), positive regulation of axon extension (GO:0045773), negative regulation of dendrite morphogenesis (GO:0050774), neuron apoptotic process (GO:0051402), regulation of cytosolic calcium ion concentration (GO:0051480), calcium ion transmembrane transport (GO:0070588), phosphatidylserine exposure on apoptotic cell surface (GO:0070782), regulation of membrane hyperpolarization (GO:1902630), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (10): actin binding (GO:0003779), calcium channel activity (GO:0005262), store-operated calcium channel activity (GO:0015279), clathrin binding (GO:0030276), actinin binding (GO:0042805), metal ion binding (GO:0046872), 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 (8): plasma membrane (GO:0005886), dendrite (GO:0030425), growth cone (GO:0030426), cation channel complex (GO:0034703), calcium channel complex (GO:0034704), neuronal cell body (GO:0043025), presynapse (GO:0098793), membrane (GO:0016020)

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
transport	2
cytoskeletal protein binding	2
cellular anatomical structure	2
metal ion transport	1
regulation of biological quality	1
system development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cell differentiation	1
generation of neurons	1
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1
positive regulation of cell growth	1
regulation of axon extension	1
positive regulation of developmental growth	1
axon extension	1
positive regulation of axonogenesis	1
negative regulation of cell projection organization	1
dendrite morphogenesis	1
regulation of dendrite morphogenesis	1
negative regulation of neurogenesis	1
apoptotic process	1
intracellular calcium ion homeostasis	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
plasma membrane phospholipid scrambling	1
phospholipid scramblase activity	1
execution phase of apoptosis	1
regulation of membrane potential	1
regulation of biological process	1
membrane hyperpolarization	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
calcium channel activity	1
protein binding	1

Protein interactions and networks

STRING

1348 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRPC5	TRPC1	P48995	983
TRPC5	STIM1	Q13586	973
TRPC5	TRPC4	Q9UBN4	970
TRPC5	TRPC3	Q13507	882
TRPC5	ENKUR	Q8TC29	834
TRPC5	SESTD1	Q86VW0	816
TRPC5	STMN2	Q93045	808
TRPC5	PKD2	Q13563	801
TRPC5	NHERF1	O14745	798
TRPC5	CALM1	P02593	794
TRPC5	CALML3	P27482	794
TRPC5	CALML5	Q9NZT1	794
TRPC5	CALML6	Q8TD86	793
TRPC5	CALML4	Q96GE6	793
TRPC5	ORAI3	Q9BRQ5	791

IntAct

124 interactions, top by confidence:

A	B	Type	Score
TRPC5	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	SHANK1	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	ARHGEF12	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	RHPN1	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	GOPC	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
NHERF2	TRPC5	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	TAMALIN	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	PARD3B	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	SNTG2	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	GRID2IP	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	FRMPD4	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	HTRA1	psi-mi:“MI:0407”(direct interaction)	0.440
SNTA1	TRPC5	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	TRPC5	psi-mi:“MI:0407”(direct interaction)	0.440
TRPC5	GIPC2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (25): TAF9 (Affinity Capture-MS), SEC24B (Affinity Capture-MS), ENKUR (Reconstituted Complex), TRPC5 (Affinity Capture-Western), TRPC5 (Affinity Capture-Western), TRPC5 (Affinity Capture-Western), STMN3 (Two-hybrid), TRPC5 (Reconstituted Complex), STMN1 (Affinity Capture-Western), STMN2 (Affinity Capture-Western), STMN4 (Affinity Capture-Western), TRPC6 (Affinity Capture-Western), TRPC3 (Affinity Capture-Western), TRPC1 (Affinity Capture-Western), TRPC5 (Reconstituted Complex)

ESM2 similar proteins: A0A1D5PXA5, O18784, O35119, O35433, O62852, P0C550, P19334, P34586, P34641, P48994, P48995, P69744, P79100, P97414, Q0JKV1, Q12324, Q5ICL9, Q61056, Q697L1, Q6R5A3, Q6RX08, Q704Y3, Q875M2, Q8GXE6, Q8K424, Q8NER1, Q8NET8, Q91WD2, Q96L42, Q9EPK8, Q9ERZ8, Q9H1D0, Q9HBA0, Q9JIP0, Q9MYV9, Q9NQA5, Q9P2G1, Q9QUQ5, Q9QX01, Q9QX29

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

6 interactions.

A	Effect	B	Mechanism
PKA	“down-regulates activity”	TRPC5	phosphorylation
PRKACA	“down-regulates quantity”	TRPC5	phosphorylation
PKA	“down-regulates quantity”	TRPC5	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	53.9×	1e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	51.3×	1e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	51.3×	1e-06
Assembly and cell surface presentation of NMDA receptors	10	47.9×	6e-13
Dopamine Neurotransmitter Release Cycle	5	46.8×	2e-06
Long-term potentiation	5	44.9×	2e-06
Neurexins and neuroligins	11	40.9×	3e-13
Protein-protein interactions at synapses	7	35.1×	6e-08

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	74.5×	2e-14
protein localization to synapse	6	58.9×	7e-08
receptor clustering	7	56.0×	7e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	7	44.5×	3e-08
cell-cell adhesion	10	13.0×	4e-07
protein-containing complex assembly	8	11.7×	2e-05
chemical synaptic transmission	7	6.9×	2e-03
protein transport	8	4.5×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	85
Likely benign	65
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

2394 predictions. Top by Δscore:

Variant	Effect	Δscore
X:111778980:ATTAC:A	donor_loss	1.0000
X:111778981:TTACC:T	donor_loss	1.0000
X:111778982:TACCT:T	donor_loss	1.0000
X:111778984:C:G	donor_loss	1.0000
X:111779081:T:TC	acceptor_gain	1.0000
X:111781933:A:AC	donor_gain	1.0000
X:111781934:C:CC	donor_gain	1.0000
X:111781944:T:TA	donor_gain	1.0000
X:111782134:TGATC:T	acceptor_gain	1.0000
X:111782135:GATCC:G	acceptor_loss	1.0000
X:111782136:ATCCT:A	acceptor_loss	1.0000
X:111782137:TC:T	acceptor_gain	1.0000
X:111782138:CCTA:C	acceptor_gain	1.0000
X:111782138:CCTAT:C	acceptor_loss	1.0000
X:111782139:C:CA	acceptor_loss	1.0000
X:111782139:C:CC	acceptor_gain	1.0000
X:111782140:T:A	acceptor_loss	1.0000
X:111834912:GCTAC:G	donor_loss	1.0000
X:111834913:CTACT:C	donor_loss	1.0000
X:111834914:TAC:T	donor_loss	1.0000
X:111834915:AC:A	donor_loss	1.0000
X:111834916:C:CA	donor_loss	1.0000
X:111834917:T:TA	donor_loss	1.0000
X:111834918:CAC:C	donor_loss	1.0000
X:111834919:A:AC	donor_gain	1.0000
X:111834919:ACGGC:A	donor_loss	1.0000
X:111834920:C:CA	donor_gain	1.0000
X:111834920:CG:C	donor_gain	1.0000
X:111834920:CGG:C	donor_gain	1.0000
X:111834920:CGGCA:C	donor_gain	1.0000

AlphaMissense

6453 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:111776974:C:G	R754P	1.000
X:111776994:C:A	K747N	1.000
X:111776994:C:G	K747N	1.000
X:111776998:A:G	L746S	1.000
X:111779048:T:A	R723S	1.000
X:111779048:T:G	R723S	1.000
X:111779049:C:G	R723T	1.000
X:111782096:A:G	W647R	1.000
X:111782096:A:T	W647R	1.000
X:111782098:A:G	L646P	1.000
X:111782106:C:A	R643S	1.000
X:111782106:C:G	R643S	1.000
X:111782107:C:A	R643M	1.000
X:111782107:C:G	R643T	1.000
X:111782112:A:C	F641L	1.000
X:111782112:A:T	F641L	1.000
X:111782113:A:G	F641S	1.000
X:111782114:A:G	F641L	1.000
X:111782117:T:C	K640E	1.000
X:111782118:C:A	W639C	1.000
X:111782118:C:G	W639C	1.000
X:111782119:C:G	W639S	1.000
X:111782120:A:G	W639R	1.000
X:111782120:A:T	W639R	1.000
X:111834937:G:A	S627F	1.000
X:111834952:G:T	A622D	1.000
X:111834955:A:T	I621N	1.000
X:111834958:A:G	L620P	1.000
X:111834958:A:T	L620Q	1.000
X:111834963:G:C	N618K	1.000

dbSNP variants (sampled 300 via entrez): RS1000020680 (X:111868586 A>G), RS1000029751 (X:111802494 A>T), RS1000031733 (X:112041419 C>A,T), RS1000038211 (X:112021853 A>G), RS1000043809 (X:111779942 A>G,T), RS1000047008 (X:111806250 C>A), RS1000058023 (X:111792888 C>A,T), RS1000067017 (X:112011149 G>A), RS1000069831 (X:112084706 T>A), RS1000072317 (X:111989417 C>A), RS1000076176 (X:111996844 C>T), RS1000080301 (X:112041126 T>C), RS1000094580 (X:111884205 C>T), RS1000108933 (X:111863563 G>A), RS1000134861 (X:111867960 T>C)

Disease associations

OMIM: gene MIM:300334 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Moderate	X-linked

Mondo (2): intellectual disability (MONDO:0001071), neurodevelopmental disorder (MONDO:0700092)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST000349_3	Smoking behavior	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004318	smoking behavior

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1250411 (SINGLE PROTEIN), CHEMBL4523660 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 100,549 (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
CHEMBL50	QUERCETIN	3	74,559
CHEMBL4466522	ZERENCOTREP	2	50
CHEMBL150	KAEMPFEROL	1	25,940

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
Pico145	Inhibition	8.89	pIC50
(-)-englerin A	Agonist	8.12	pEC50
HC-070	Antagonist	8.03	pIC50
AM237	Activation	7.7	pEC50
tonantzitlolone	Activation	7.08	pEC50
AM12	Inhibition	6.55	pIC50
GFB-8438	Inhibition	6.5	pIC50
galangin	Channel blocker	6.35	pKi
Ca2+	Activator	6.2	pEC50
clemizole	Channel blocker	5.96	pIC50
KB-R7943	Inhibition	5.86	pIC50
BTD	Activation	5.85	pEC50
progesterone	Inhibition	5.3	pIC50
M084	Inhibition	5.09	pIC50
riluzole	Activation	5.04	pEC50
ML204	Channel blocker	5.0	pIC50
bromoenol lactone	Inhibition	4.97	pIC50
methylprednisolone	Activation	4.92	pEC50
AC1903	Inhibition	4.83	pIC50
2-APB	Antagonist	4.7	pIC50
rosiglitazone	Activation	4.51	pEC50
Mg2+	Inhibition	3.34	pIC50

Binding affinities (BindingDB)

2 measured of 6 human assays (6 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-(4-chlorophenyl)-5-[(4-chlorophenyl)methyl]-3-(3-hydroxypropyl)-1-methyl-4a,7a-dihydrothieno[2,3-d]pyrimidine-2,4-dione	IC50	1.84 nM	US-9447114: Thieno- and furo[2,3-d]pyrimidine-2,4[1H,3H]-dione derivatives
6-(4-chlorophenyl)-3-(3-hydroxypropyl)-1,5-dimethyl-4a,7a-dihydrothieno[2,3-d]pyrimidine-2,4-dione	IC50	15.7 nM	US-9447114: Thieno- and furo[2,3-d]pyrimidine-2,4[1H,3H]-dione derivatives

ChEMBL bioactivities

188 potent at pChembl≥5 of 202 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.72	IC50	0.19	nM	ZERENCOTREP
9.28	IC50	0.52	nM	CHEMBL4546097
9.00	IC50	1	nM	CHEMBL6177762
8.89	IC50	1.3	nM	ZERENCOTREP
8.77	IC50	1.7	nM	CHEMBL6165871
8.73	IC50	1.84	nM	CHEMBL3945449
8.72	IC50	1.91	nM	CHEMBL3920228
8.70	IC50	2	nM	CHEMBL5598527
8.58	IC50	2.64	nM	CHEMBL4466158
8.57	IC50	2.69	nM	CHEMBL4525688
8.44	IC50	3.6	nM	CHEMBL6174203
8.42	IC50	3.8	nM	CHEMBL6164489
8.40	IC50	4	nM	CHEMBL6173915
8.40	IC50	4	nM	CHEMBL6162804
8.40	IC50	4	nM	CHEMBL6169683
8.38	IC50	4.2	nM	CHEMBL6174430
8.34	IC50	4.6	nM	CHEMBL6167404
8.30	IC50	5	nM	CHEMBL5597024
8.28	IC50	5.3	nM	CHEMBL4451083
8.26	IC50	5.5	nM	CHEMBL6173536
8.22	IC50	6	nM	CHEMBL6169487
8.22	IC50	6	nM	CHEMBL6177854
8.21	IC50	6.1	nM	CHEMBL6175851
8.15	IC50	7	nM	CHEMBL6175169
8.12	EC50	7.59	nM	ENGLERIN A
8.10	IC50	8	nM	CHEMBL4752870
8.10	IC50	8	nM	CHEMBL5597024
8.10	IC50	8	nM	CHEMBL5597219
8.10	IC50	8	nM	CHEMBL6177231
8.08	IC50	8.37	nM	CHEMBL4562137
8.08	IC50	8.3	nM	CHEMBL4752870
8.05	IC50	9	nM	CHEMBL4466158
8.05	IC50	9	nM	CHEMBL5597910
8.05	IC50	9	nM	CHEMBL5596183
8.03	IC50	9.3	nM	CHEMBL4546097
8.00	IC50	10	nM	CHEMBL4546097
7.92	IC50	12	nM	CHEMBL6171494
7.92	IC50	12	nM	CHEMBL6176643
7.85	IC50	14.07	nM	CHEMBL5201831
7.82	IC50	15	nM	CHEMBL6175520
7.80	IC50	15.7	nM	CHEMBL3948028
7.75	IC50	18	nM	CHEMBL6166624
7.72	IC50	19	nM	CHEMBL5590573
7.64	IC50	23	nM	CHEMBL5596485
7.63	IC50	23.3	nM	CHEMBL4464289
7.60	IC50	25	nM	CHEMBL6176893
7.58	IC50	26	nM	CHEMBL6176759
7.57	IC50	27	nM	CHEMBL3928277
7.57	IC50	27	nM	CHEMBL3942647
7.57	IC50	27	nM	CHEMBL3942703

PubChem BioAssay actives

130 with measured affinity, of 315 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
7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-3-methyl-8-[3-(trifluoromethoxy)phenoxy]purine-2,6-dione	1578708: Inhibition of human TRPC5/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	0.0002	uM
8-(3-chlorophenoxy)-7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-3-methylpurine-2,6-dione	1578714: Inhibition of human TRPC5 expressed in human T-REx-293 cells assessed as reduction in lanthanum-activated TRPC5-mediated currents by whole-cell patch clamp method	ic50	0.0005	uM
6-butoxy-5-[(4-fluorophenyl)methyl]-3-(3-hydroxypropyl)-1-methylquinazoline-2,4-dione	1626391: Inhibition of TRPC5 (unknown origin) transfected in HEK293/TREx cells assessed as reduction of rise in intracellular Ca2+ concentration after 60 to 80 mins by Fluo4 cell-based fluorescence assay	ic50	0.0010	uM
5-benzyl-3-(3-hydroxypropyl)-1-methyl-6-[3-(trifluoromethoxy)phenoxy]quinazoline-2,4-dione	1626392: Inhibition of TRPC5 (unknown origin) transfected in HEK293/TREx cells assessed as blocking of inward/outward currents after 20 to 48 hrs in presence of LaCl3 by patch clamp assay	ic50	0.0010	uM
5-chloro-4-[3-[1-[4-fluoro-2-(trifluoromethyl)phenyl]ethenyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-1H-pyridazin-6-one	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.0020	uM
5-[(4-fluorophenyl)methyl]-3-(3-hydroxypropyl)-1-methyl-6-propan-2-yloxyquinazoline-2,4-dione	1626391: Inhibition of TRPC5 (unknown origin) transfected in HEK293/TREx cells assessed as reduction of rise in intracellular Ca2+ concentration after 60 to 80 mins by Fluo4 cell-based fluorescence assay	ic50	0.0026	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	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.0050	uM
5-benzyl-3-(3-hydroxypropyl)-1-methyl-6-[3-(trifluoromethoxy)phenyl]quinazoline-2,4-dione	1626392: Inhibition of TRPC5 (unknown origin) transfected in HEK293/TREx cells assessed as blocking of inward/outward currents after 20 to 48 hrs in presence of LaCl3 by patch clamp assay	ic50	0.0053	uM
[(1S,2R,5R,6R,7S,8R,10R)-10-(2-hydroxyacetyl)oxy-1,5-dimethyl-8-propan-2-yl-11-oxatricyclo[6.2.1.02,6]undecan-7-yl] (E)-3-phenylprop-2-enoate	1893735: Agonist activity at human TRPC5 stably expressed in HEK293 cells assessed as increase in calcium flux by Fura-2AM dye based fluorescence plate reader assay	ec50	0.0076	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	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.0080	uM
5-chloro-4-[3-[(4-fluoro-2-methylphenyl)-methoxymethyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-1H-pyridazin-6-one	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.0080	uM
5-[(4-fluorophenyl)methyl]-3-(3-hydroxypropyl)-6-methoxy-1-methylquinazoline-2,4-dione	1626392: Inhibition of TRPC5 (unknown origin) transfected in HEK293/TREx cells assessed as blocking of inward/outward currents after 20 to 48 hrs in presence of LaCl3 by patch clamp assay	ic50	0.0084	uM
5-chloro-4-[3-[[4-fluoro-2-(trifluoromethyl)phenyl]-methoxymethyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-1H-pyridazin-6-one	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.0090	uM
5-chloro-4-[3-[methoxy-[2-(trifluoromethyl)phenyl]methyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-1H-pyridazin-6-one	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.0090	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	1889509: Inhibition of human TRPC5 channel expressed in HEK293 cells assessed as inhibition of EA-evoked channel current measured at +80 mV by whole-cell voltage clamp assay	ic50	0.0141	uM
5-chloro-4-[3-[[4-fluoro-2-(trifluoromethyl)phenyl]-(trideuteriomethoxy)methyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-1H-pyridazin-6-one	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.0190	uM
5-chloro-4-[3-[[5-fluoro-2-(trifluoromethyl)phenyl]-methoxymethyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-1H-pyridazin-6-one	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.0230	uM
5-benzyl-3-(3-hydroxypropyl)-6-methoxy-1-methylquinazoline-2,4-dione	1626392: Inhibition of TRPC5 (unknown origin) transfected in HEK293/TREx cells assessed as blocking of inward/outward currents after 20 to 48 hrs in presence of LaCl3 by patch clamp assay	ic50	0.0233	uM
4-[2-bromo-3-[(2-chloro-4-fluorophenyl)-methoxymethyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-5-chloro-1H-pyridazin-6-one	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.0360	uM
4-[3-[(2-bromo-4-fluorophenyl)-methoxymethyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-5-chloro-1H-pyridazin-6-one	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.0380	uM
4-[2-bromo-3-[[4-fluoro-2-(trifluoromethyl)phenyl]-methoxymethyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-5-chloro-1H-pyridazin-6-one	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.0450	uM
5-chloro-4-[3-oxo-4-[[2-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]-1H-pyridazin-6-one	1889509: Inhibition of human TRPC5 channel expressed in HEK293 cells assessed as inhibition of EA-evoked channel current measured at +80 mV by whole-cell voltage clamp assay	ic50	0.0501	uM
5-chloro-4-[3-[(4-fluoro-2-nitrophenyl)-methoxymethyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-1H-pyridazin-6-one	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.0670	uM
5-chloro-4-[3-[1-[4-fluoro-2-(trifluoromethyl)phenyl]ethyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-1H-pyridazin-6-one	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.0800	uM
5-chloro-4-[3-[(2,4-dichlorophenyl)-methoxymethyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-1H-pyridazin-6-one	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.0890	uM
3-chloro-4-[4-(2-cyclopropyl-4-fluorophenoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]pyrrole-2,5-dione	1889504: Inhibition of TRPC5 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	0.1110	uM
3-chloro-4-[4-[4-fluoro-2-(trifluoromethyl)phenoxy]-2-methyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]pyrrole-2,5-dione	1889504: Inhibition of TRPC5 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	0.1250	uM
5-chloro-4-[3-[[4-fluoro-2-(trifluoromethyl)phenyl]-methoxymethyl]-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-1H-pyridazin-6-one	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.1300	uM
5-chloro-4-[3-[[2-fluoro-6-(trifluoromethyl)phenyl]-methoxymethyl]-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-1H-pyridazin-6-one	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.1350	uM
5-benzyl-3-(3-hydroxypropyl)-1-methyl-6-[3-(trifluoromethoxy)phenyl]pyrido[3,4-d]pyrimidine-2,4-dione	1578721: Inhibition of TRPC5 (unknown origin) expressed in HEK293/TREx cells assessed as reduction in intracellular calcium level measured for 3 mins by fluo4 dye-based fluorescence assay	ic50	0.1950	uM
6-(3-chlorophenyl)-3-(3-hydroxypropyl)-1-methyl-5-(3-methylbutyl)pyrido[3,4-d]pyrimidine-2,4-dione	1578721: Inhibition of TRPC5 (unknown origin) expressed in HEK293/TREx cells assessed as reduction in intracellular calcium level measured for 3 mins by fluo4 dye-based fluorescence assay	ic50	0.1950	uM
6-(3-chlorophenoxy)-5-[(4-chlorophenyl)methyl]-3-(3-hydroxypropyl)-1-methylpyrido[3,4-d]pyrimidine-2,4-dione	1578721: Inhibition of TRPC5 (unknown origin) expressed in HEK293/TREx cells assessed as reduction in intracellular calcium level measured for 3 mins by fluo4 dye-based fluorescence assay	ic50	0.1950	uM
3-(3-hydroxypropyl)-1-methyl-6-(2-propan-2-ylphenyl)pyrido[3,4-d]pyrimidine-2,4-dione	1578721: Inhibition of TRPC5 (unknown origin) expressed in HEK293/TREx cells assessed as reduction in intracellular calcium level measured for 3 mins by fluo4 dye-based fluorescence assay	ic50	0.1950	uM
5-[(4-chlorophenyl)methyl]-3-(3-hydroxypropyl)-1-methyl-6-(2-propan-2-ylphenyl)pyrido[3,4-d]pyrimidine-2,4-dione	1578721: Inhibition of TRPC5 (unknown origin) expressed in HEK293/TREx cells assessed as reduction in intracellular calcium level measured for 3 mins by fluo4 dye-based fluorescence assay	ic50	0.1950	uM
3-(3-hydroxypropyl)-1-methyl-5-(3-methylbutyl)-6-(2-propan-2-ylphenyl)pyrido[3,4-d]pyrimidine-2,4-dione	1578721: Inhibition of TRPC5 (unknown origin) expressed in HEK293/TREx cells assessed as reduction in intracellular calcium level measured for 3 mins by fluo4 dye-based fluorescence assay	ic50	0.1950	uM
6-(4-chlorophenyl)-3-(3-hydroxypropyl)-1-methyl-5-(3-methylbutyl)pyrido[3,4-d]pyrimidine-2,4-dione	1578721: Inhibition of TRPC5 (unknown origin) expressed in HEK293/TREx cells assessed as reduction in intracellular calcium level measured for 3 mins by fluo4 dye-based fluorescence assay	ic50	0.1950	uM
3-[6-(4-chlorophenyl)-5-[(4-chlorophenyl)methyl]-1-methyl-2,4-dioxopyrido[3,4-d]pyrimidin-3-yl]propyl hydrogen carbonate	1578721: Inhibition of TRPC5 (unknown origin) expressed in HEK293/TREx cells assessed as reduction in intracellular calcium level measured for 3 mins by fluo4 dye-based fluorescence assay	ic50	0.1950	uM
5-chloro-4-[3-[(2-chloro-4-fluorophenyl)-methoxymethyl]-2-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl]-1H-pyridazin-6-one	2119884: Inhibition of TRPC5 (unknown origin) expressed in HEK293 cells assessed as reduction in englerin A stimulated Ca2+ influx by FLIPR assay	ic50	0.2490	uM
2-(2-bromophenyl)-3,5,7-trihydroxychromen-4-one	1578736: Inhibition of human TRPC5 expressed in HEK293 cells assessed as reduction in gadolinium-induced calcium entry after 30 mins by fura-2 dye based fluorescence assay	ic50	0.2800	uM
3-chloro-4-[4-(2-chloro-4-fluorophenoxy)-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]pyrrole-2,5-dione	1889504: Inhibition of TRPC5 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	0.2800	uM
N-[4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl]-4-methylthiadiazole-5-carboxamide	1578740: Inhibition of TRPC5 (unknown origin)	ic50	0.3000	uM
3-chloro-4-[4-[4-chloro-2-(trifluoromethyl)phenoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]pyrrole-2,5-dione	1889504: Inhibition of TRPC5 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	0.3140	uM
5-chloro-4-[4-[(2,6-dimethylphenyl)methyl]-3-oxopiperazin-1-yl]-1H-pyridazin-6-one	1611653: Inhibition of rosiglitazone-activated human TRPC5 channel expressed in HEK293 cells assessed as reduction in Ca2+ current measured at +80 mV with holding potential of -60 mV by Q-patch clamp assay	ic50	0.3800	uM
5-[(4-chlorophenyl)methyl]-3-(3-hydroxypropyl)-1-methyl-6-[3-(trifluoromethoxy)phenyl]pyrrolo[3,2-d]pyrimidine-2,4-dione	1578721: Inhibition of TRPC5 (unknown origin) expressed in HEK293/TREx cells assessed as reduction in intracellular calcium level measured for 3 mins by fluo4 dye-based fluorescence assay	ic50	0.4080	uM
5-[(4-chlorophenyl)methyl]-3-(3-hydroxypropyl)-1,7-dimethylpyrrolo[3,2-d]pyrimidine-2,4-dione	1578721: Inhibition of TRPC5 (unknown origin) expressed in HEK293/TREx cells assessed as reduction in intracellular calcium level measured for 3 mins by fluo4 dye-based fluorescence assay	ic50	0.4080	uM
6-(3-chlorophenyl)-5-[(4-chlorophenyl)methyl]-3-(3-hydroxypropyl)-1-methylpyrrolo[3,2-d]pyrimidine-2,4-dione	1578721: Inhibition of TRPC5 (unknown origin) expressed in HEK293/TREx cells assessed as reduction in intracellular calcium level measured for 3 mins by fluo4 dye-based fluorescence assay	ic50	0.4080	uM
3-(3-hydroxypropyl)-1,5,7-trimethyl-6-[3-(trifluoromethoxy)phenyl]pyrrolo[3,2-d]pyrimidine-2,4-dione	1578721: Inhibition of TRPC5 (unknown origin) expressed in HEK293/TREx cells assessed as reduction in intracellular calcium level measured for 3 mins by fluo4 dye-based fluorescence assay	ic50	0.4080	uM
5-[(4-chlorophenyl)methyl]-3-(3-hydroxypropyl)-1,7-dimethyl-6-[3-(trifluoromethoxy)phenyl]pyrrolo[3,2-d]pyrimidine-2,4-dione	1578721: Inhibition of TRPC5 (unknown origin) expressed in HEK293/TREx cells assessed as reduction in intracellular calcium level measured for 3 mins by fluo4 dye-based fluorescence assay	ic50	0.4080	uM
7-(3-chlorophenyl)-5-[(4-chlorophenyl)methyl]-3-(3-hydroxypropyl)-1-methylpyrrolo[3,2-d]pyrimidine-2,4-dione	1578721: Inhibition of TRPC5 (unknown origin) expressed in HEK293/TREx cells assessed as reduction in intracellular calcium level measured for 3 mins by fluo4 dye-based fluorescence assay	ic50	0.4080	uM
3-(3-hydroxypropyl)-1,7-dimethyl-6-[3-(trifluoromethoxy)phenyl]-5H-pyrrolo[3,2-d]pyrimidine-2,4-dione	1578721: Inhibition of TRPC5 (unknown origin) expressed in HEK293/TREx cells assessed as reduction in intracellular calcium level measured for 3 mins by fluo4 dye-based fluorescence assay	ic50	0.4080	uM

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
2-aminoethoxydiphenyl borate	decreases reaction, increases activity, increases reaction, increases transport	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases mutagenesis	2
Calcium	affects transport, decreases reaction, increases reaction, increases transport, affects reaction	2
aristolochic acid I	increases expression	1
sodium arsenite	increases expression	1
1-oleoyl-2-acetylglycerol	affects reaction, affects transport	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	decreases reaction, increases reaction, increases transport	1
Ascorbic Acid	decreases reaction, increases reaction, increases transport	1
Atrazine	increases expression	1
Carbachol	increases reaction, increases transport, decreases reaction	1
4-Chloromercuribenzenesulfonate	increases activity	1
Diethylhexyl Phthalate	decreases expression	1
Diethylstilbestrol	decreases reaction, increases transport	1
Succimer	increases activity	1
Dithiothreitol	decreases reaction, increases activity	1
Gadolinium	decreases reaction, increases reaction, increases transport	1
Gallic Acid	decreases reaction, increases reaction, increases transport	1
Hydrogen Peroxide	decreases reaction, increases reaction, increases transport	1
Lysophosphatidylcholines	increases reaction, increases transport, decreases reaction	1
Mercuric Chloride	decreases reaction, increases activity, affects response to substance	1
Methylmercury Compounds	decreases reaction, increases activity	1
Aflatoxin B1	decreases methylation	1

ChEMBL screening assays

71 unique, capped per target: 70 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1252884	Binding	Induction of S-nitrosylation of TRPC5 in HEK cells assessed as increase in Ca2+ level from extracellular space at 300 uM	Nitric oxide activates TRP channels by cysteine S-nitrosylation. — Nat Chem Biol
CHEMBL4622718	ADMET	Agonist activity at human TRPC5 expressed in HEK293 Tet cells assessed as increase in intracellular calcium level at 10 nM 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)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays