TRPV4

Summary

TRPV4 (transient receptor potential cation channel subfamily V member 4, HGNC:18083) is a protein-coding gene on chromosome 12q24.11, encoding Transient receptor potential cation channel subfamily V member 4 (Q9HBA0). Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity.

This gene encodes a member of the OSM9-like transient receptor potential channel (OTRPC) subfamily in the transient receptor potential (TRP) superfamily of ion channels. The encoded protein is a Ca2+-permeable, nonselective cation channel that is thought to be involved in the regulation of systemic osmotic pressure. Mutations in this gene are the cause of spondylometaphyseal and metatropic dysplasia and hereditary motor and sensory neuropathy type IIC. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 59341 — RefSeq curated summary.

At a glance

• Gene–disease (curated): TRPV4-related bone disorder (Definitive, ClinGen) — +10 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 1,323 total — 33 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 214
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• Transcription factor: yes — 13 downstream targets (CollecTRI)
• MANE Select transcript: NM_021625

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18083
Approved symbol	TRPV4
Name	transient receptor potential cation channel subfamily V member 4
Location	12q24.11
Locus type	gene with protein product
Status	Approved
Aliases	OTRPC4, TRP12, VROAC, VRL-2, VR-OAC, CMT2C
Ensembl gene	ENSG00000111199
Ensembl biotype	protein_coding
OMIM	605427
Entrez	59341

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 9 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000261740, ENST00000418703, ENST00000536838, ENST00000537083, ENST00000538125, ENST00000541794, ENST00000544971, ENST00000674908, ENST00000675533, ENST00000675670, ENST00000676376, ENST00000909280, ENST00000909281

RefSeq mRNA: 5 — MANE Select: NM_021625 NM_001177428, NM_001177431, NM_001177433, NM_021625, NM_147204

CCDS: CCDS53827, CCDS53828, CCDS53829, CCDS9134, CCDS9135

Canonical transcript exons

ENST00000261740 — 16 exons

Exon	Start	End
ENSE00000754963	109793527	109793600
ENSE00000754964	109793930	109794022
ENSE00000754970	109794329	109794487
ENSE00000754972	109796525	109796704
ENSE00001128628	109798614	109798912
ENSE00001128637	109800618	109800758
ENSE00001128642	109802991	109803143
ENSE00001128645	109808296	109808468
ENSE00001225767	109814411	109814827
ENSE00002251935	109783089	109783778
ENSE00003503892	109786710	109786837
ENSE00003517194	109792652	109792817
ENSE00003574740	109784316	109784437
ENSE00003607099	109792363	109792429
ENSE00003616427	109788400	109788716
ENSE00003897167	109833350	109833398

Expression profiles

Bgee: expression breadth ubiquitous, 171 present calls, max score 92.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1.9693 / max 72.3883, expressed in 959 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133199	1.9693	959

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	92.60	gold quality
lower esophagus mucosa	UBERON:0035834	87.57	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	86.78	gold quality
buccal mucosa cell	CL:0002336	83.77	gold quality
minor salivary gland	UBERON:0001830	83.26	gold quality
saliva-secreting gland	UBERON:0001044	82.07	gold quality
stromal cell of endometrium	CL:0002255	81.99	gold quality
mouth mucosa	UBERON:0003729	80.69	gold quality
oocyte	CL:0000023	80.45	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.40	gold quality
adult mammalian kidney	UBERON:0000082	79.98	gold quality
metanephros cortex	UBERON:0010533	79.76	gold quality
esophagus mucosa	UBERON:0002469	79.22	gold quality
tibia	UBERON:0000979	77.47	gold quality
bronchial epithelial cell	CL:0002328	77.27	gold quality
epithelium of bronchus	UBERON:0002031	77.24	gold quality
bronchus	UBERON:0002185	76.62	gold quality
skin of abdomen	UBERON:0001416	76.29	gold quality
skin of leg	UBERON:0001511	76.26	gold quality
right lobe of liver	UBERON:0001114	76.19	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	75.27	gold quality
secondary oocyte	CL:0000655	75.13	gold quality
mucosa of paranasal sinus	UBERON:0005030	74.86	silver quality
nasal cavity mucosa	UBERON:0001826	74.77	gold quality
zone of skin	UBERON:0000014	74.02	gold quality
parotid gland	UBERON:0001831	73.97	silver quality
right uterine tube	UBERON:0001302	73.83	gold quality
kidney	UBERON:0002113	73.31	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.60	gold quality
cortex of kidney	UBERON:0001225	71.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.18

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

13 targets.

Target	Regulation
ADRB3	Repression
CCL7	Activation
CIDEA	Repression
COX4I1	Repression
COX5A	Repression
COX7A1	Repression
PPARGC1A	Repression
PPARGC1B	Repression
TIMP1	Activation
TLR2	Activation
TNF	Activation
UCP1	Repression
VCAM1	Activation

Upstream regulators (CollecTRI, top): PGR, TBPL1

miRNA regulators (miRDB)

19 targeting TRPV4, 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-5692A	100.00	74.40	6850
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-128-1-5P	99.33	60.46	332
HSA-MIR-128-2-5P	99.33	60.83	311
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-4660	97.79	67.44	1328
HSA-MIR-3144-5P	97.64	65.45	646
HSA-MIR-6762-5P	96.55	64.62	972
HSA-MIR-6845-5P	96.55	64.65	969
HSA-MIR-2861	95.24	65.47	1056
HSA-MIR-6503-3P	93.87	66.39	348

Literature-anchored findings (GeneRIF, showing 40)

• Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives. (PMID:11827975)
• TRPV4 is a channel-forming protein that response to mutationa in its putative pore region with change in premeability and block. (PMID:12093812)
• TRPV4 is a functional temperature-sensing channel in native endothelium, that is likely involved in temperature-dependent Ca(2+) signaling (PMID:12354759)
• TRPV4 activity is tightly controlled by intracellular Ca2+. Ca2+ entry increases both the rate and extent of channel activation by a calmodulin-dependent mechanism. (PMID:12724311)
• functional TRPV4 is expressed in human airway smooth muscle cells and may act as an osmolarity sensor in the airway. (PMID:15075247)
• results suggest that defective regulatory volume decrease (RVD) in cystic fibrosis airway epithelia might be caused by the absence of transient receptor potential cationic channel TRPV4-mediated Calcium(2+) signal (PMID:15489228)
• TRPV4 channel is involved in the coupling of fluid viscosity changes to epithelial ciliary activity. (PMID:15753126)
• Ankyrin domains are necessary for oligomerization of TRPV4; and lack of TRPV4 oligomerization determines its accumulation in the endoplasmic reticulum. (PMID:16293632)
• there is a single high-probability N-linked glycosylation site in TRP4 that faces the extracellular milieu and is phylogenetically conserved (PMID:16368742)
• data indicate that transient receptor potential channel 4(TRPV4) is functionally regulated by WNK family kinases 1 and 4 at the level of cell surface expression (PMID:16403833)
• TRPV4 participates in hypotonic reduction of AQP5. (PMID:16537379)
• studies with suggest a role for the channel in the regulation of body osmolarity, mechanosensation, temperature sensing, vascular regulation and, possibly, hearing–{REVIEW} (PMID:17217058)
• TRPM3 may have diverse cellular functions depending on the expression of a particular variant while TRPV4 plays a central role in epithelial homoeostasis by modulating epithelial barrier function [review] (PMID:17233610)
• this study shows for the first time that TRPV4 and actin intimately associate within living cells. (PMID:17374521)
• accumulation of TRPV1 and TRPV3 in peripheral nerves after injury, in spared axons, matches our previously reported changes in avulsed DRG. (PMID:17521436)
• OS-9 regulates the secretory transport of TRPV4 and appears to protect TRPV4 subunits from the precocious ubiquitination and ER-associated degradation. (PMID:17932042)
• PACSIN 3 acts as an auxiliary protein of TRPV4 channel that not only affects the channel’s subcellular localization but also modulates its function in a stimulus-specific manner. (PMID:18174177)
• altered expression of the channel in CRS and presumed expression of TRPV4 in secretory cells of the mucosa indicate a potential role in mucus homeostasis and CRS pathogenesis. (PMID:18284852)
• low-level shear stress enhances epithelial barrier function, an effect that requires serial activation of the transient receptor potential vanilloid (TRPV) 4 and L-type voltage-gated calcium channel (VGCC) and an increase in intracellular calcium. (PMID:18305162)
• These data indicate that the C-terminus of TRPV4 is required for oligomerization, which takes place in the endoplasmic reticulum and precedes plasma membrane trafficking. (PMID:18307101)
• Data indicate that TRPV4 contributes to mechanically evoked visceral pain in inflammatory bowel disease. (PMID:18343379)
• There is TRPV4 functional expression in human corneal epithelial cells. (PMID:18355916)
• Study shows that inositol trisphosphate (IP3), sensitizes TRPV4 to epoxyeicosatrienoic acid but not to other TRPV4 physiological stimuli such as warm temperature, an effect that requires a functional IP3 receptor. (PMID:18378772)
• play a role in pathophysiology of neurogenic inflammation. (PMID:18552442)
• In two families with an autosomal dominant form of brachyolmia study identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. (PMID:18587396)
• In cultured human endothelial cells, exposure to fluid shear stress induced the translocation of the TRPV4 channel from a perinuclear localization to the cell membrane. (PMID:18682435)
• Messenger RNA transcripts of TRPVs 1 through 4 are detected for the first time in human pulmonary artery smooth muscle cells. (PMID:18787888)
• Report TRPV4-like non-selective cation currents in cultured aortic myocytes. (PMID:18845910)
• relative gene expression ofTRPV1-4 in leukocytes is: TRPV3 < TRPV4, TRPV1 and TRPV2; leukocytes in hyposensitive subjects showed up-regulation of TRPV1, which was almost doubly expressed (PMID:18983665)
• These data demonstrate a functional interaction between TRPV4 and F-actin in sensing hypotonicity and the onset of regulatory volume decrease. (PMID:19027987)
• that tyrosine phosphorylation of TRPV4 represents an important modulatory mechanism, which may underlie the recently described function of TRPV4 in inflammatory hyperalgesia (PMID:19033444)
• TRPV4 is assumed to play a role as an osmoreceptor in cell and fluid volume regulation in the human endolymphatic sac. (PMID:19066426)
• Mutations in TRPV4 produce a phenotypic spectrum of skeletal dysplasias from the mild autosomal-dominant brachyolmia to SMDK to autosomal-dominant metatropic dysplasia, suggesting that these disorders should be grouped into a new bone dysplasia family. (PMID:19232556)
• Polymorphisms in the TRPV4 gene are associated with chronic obstructive pulmonary disease. (PMID:19279160)
• TRPV4 channels mediate cyclic strain-induced endothelial cell reorientation through integrin-to-integrin signaling. (PMID:19359599)
• Data suggest that PKC and PKA enhance activation of the TRPV4 ion channel by phosphorylation at specific sites and that phosphorylation depends on assembly of PKC and PKA by AKAP79 into a signaling complex with TRPV4. (PMID:19661060)
• the loss-of-function nonsynonymous polymorphism in the osmoregulatory TRPV4 gene is associated with human hyponatremia (PMID:19666518)
• our data report the regulation of TRPV4 expression by progesterone, a process that requires a functional progesterone receptor (PMID:19701771)
• Its activation contributes to neural transmission of cough reflex. (review) (PMID:19749483)
• TRPV4 mutations can also cause a degenerative disorder of the peripheral nerves. (PMID:20037586)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	trpv4	ENSDARG00000061941
mus_musculus	Trpv4	ENSMUSG00000014158
rattus_norvegicus	Trpv4	ENSRNOG00000001195
drosophila_melanogaster		FBGN0036414
drosophila_melanogaster	iav	FBGN0086693
caenorhabditis_elegans		WBGENE00003841
caenorhabditis_elegans		WBGENE00003889

Paralogs (5): TRPV5 (ENSG00000127412), TRPV6 (ENSG00000165125), TRPV3 (ENSG00000167723), TRPV2 (ENSG00000187688), TRPV1 (ENSG00000196689)

Protein

Protein identifiers

Transient receptor potential cation channel subfamily V member 4 — Q9HBA0 (reviewed: Q9HBA0)

Alternative names: Osm-9-like TRP channel 4, Transient receptor potential protein 12, Vanilloid receptor-like channel 2, Vanilloid receptor-like protein 2, Vanilloid receptor-related osmotically-activated channel

All UniProt accessions (3): A0A6Q8PFZ3, Q9HBA0, F5H6Q4

UniProt curated annotations — full annotation on UniProt →

Function. Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification. Also activated by heat, low pH, citrate and phorbol esters. Increase of intracellular Ca(2+) potentiates currents. Channel activity seems to be regulated by a calmodulin-dependent mechanism with a negative feedback mechanism. Promotes cell-cell junction formation in skin keratinocytes and plays an important role in the formation and/or maintenance of functional intercellular barriers. Acts as a regulator of intracellular Ca(2+) in synoviocytes. Plays an obligatory role as a molecular component in the nonselective cation channel activation induced by 4-alpha-phorbol 12,13-didecanoate and hypotonic stimulation in synoviocytes and also regulates production of IL-8. Together with PKD2, forms mechano- and thermosensitive channels in cilium. Negatively regulates expression of PPARGC1A, UCP1, oxidative metabolism and respiration in adipocytes. Regulates expression of chemokines and cytokines related to pro-inflammatory pathway in adipocytes. Together with AQP5, controls regulatory volume decrease in salivary epithelial cells. Required for normal development and maintenance of bone and cartilage. In its inactive state, may sequester DDX3X at the plasma membrane. When activated, the interaction between both proteins is affected and DDX3X relocalizes to the nucleus. In neurons of the central nervous system, could play a role in triggering voluntary water intake in response to increased sodium concentration in body fluid. Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification. Also activated by phorbol esters. Has the same channel activity as isoform 1, and is activated by the same stimuli. Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification. Also activated by phorbol esters. Has the same channel activity as isoform 1, and is activated by the same stimuli. Lacks channel activity, due to impaired oligomerization and intracellular retention. Lacks channel activity, due to impaired oligomerization and intracellular retention. Lacks channel activity, due to impaired oligomerization and intracellular retention. (Microbial infection) Facilitates hepatitis C virus (HCV) replication, possibly through its action on DDX3X. (Microbial infection) Facilitates Dengue virus (DENV) replication, possibly through its action on DDX3X. (Microbial infection) Facilitates Zika virus (ZIKV) replication, possibly through its action on DDX3X.

Subunit / interactions. Homotetramer. Self-associates in an isoform-specific manner. Isoform 1 and isoform 5 can oligomerize, but isoform 2, isoform 4 and isoform 6 cannot oligomerize. Interacts with calmodulin. Interacts with Map7 and Src family Tyr protein kinases LYN, SRC, FYN, HCK, LCK and YES. Interacts with CTNNB1. The TRPV4 and CTNNB1 complex can interact with CDH1. Interacts with PACSIN1, PACSIN2 and PACSIN3 (via SH3 domain). Part of a complex containing MLC1, AQP4, HEPACAM and ATP1B1. Interacts with ITPR3. Interacts with AQP5; the interaction is probably indirect and regulates TRPV4 activation by hypotonicity. Interacts with ANO1. Interacts (via C-terminus) with PKD2 (via C-terminus). Interacts with DDX3X; this interaction is decreased when the channel is activated.

Subcellular location. Cell membrane. Apical cell membrane. Cell junction. Adherens junction. Cell projection. Cilium Cell membrane Cell membrane Endoplasmic reticulum Endoplasmic reticulum Endoplasmic reticulum.

Tissue specificity. Found in the synoviocytes from patients with (RA) and without (CTR) rheumatoid arthritis (at protein level).

Post-translational modifications. N-glycosylated.

Disease relevance. Brachyolmia 3 (BCYM3) [MIM:113500] A form of brachyolmia, a clinically and genetically heterogeneous skeletal dysplasia primarily affecting the spine and characterized by a short trunk, short stature, and platyspondyly. BCYM3 is an autosomal dominant form with severe scoliosis with or without kyphosis, and flattened irregular cervical vertebrae. The disease is caused by variants affecting the gene represented in this entry. Spondylometaphyseal dysplasia Kozlowski type (SMDK) [MIM:184252] A form of spondylometaphyseal dysplasia, a group of short stature disorders distinguished by abnormalities in the vertebrae and the metaphyses of the tubular bones. It is characterized by postnatal dwarfism, significant scoliosis and mild metaphyseal abnormalities in the pelvis. The vertebrae exhibit platyspondyly and overfaced pedicles. The disease is caused by variants affecting the gene represented in this entry. Metatropic dysplasia (MTD) [MIM:156530] A severe spondyloepimetaphyseal dysplasia characterized by short limbs with limitation and enlargement of joints and usually severe kyphoscoliosis. Radiologic features include severe platyspondyly, severe metaphyseal enlargement and shortening of long bones. The disease is caused by variants affecting the gene represented in this entry. Neuronopathy, distal hereditary motor, autosomal dominant 8 (HMND8) [MIM:600175] A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. The disease is caused by variants affecting the gene represented in this entry. Charcot-Marie-Tooth disease, axonal, autosomal dominant, type 2C (CMT2C) [MIM:606071] An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. The disease is caused by variants affecting the gene represented in this entry. Scapuloperoneal spinal muscular atrophy (SPSMA) [MIM:181405] A clinically variable neuromuscular disorder characterized by neurogenic scapuloperoneal amyotrophy, laryngeal palsy, congenital absence of muscles, progressive scapuloperoneal atrophy and progressive distal weakness and amyotrophy. The disease is caused by variants affecting the gene represented in this entry. Spondyloepiphyseal dysplasia, Maroteaux type (SEDM) [MIM:184095] An autosomal dominant, clinically variable spondyloepiphyseal dysplasia with manifestations limited to the musculoskeletal system. Clinical features include short stature, brachydactyly, platyspondyly, short and stubby hands and feet, epiphyseal hypoplasia of the large joints, and iliac hypoplasia. Intelligence is normal. The disease is caused by variants affecting the gene represented in this entry. Parastremmatic dwarfism (PSTD) [MIM:168400] A bone dysplasia characterized by severe dwarfism, kyphoscoliosis, distortion and bowing of the extremities, and contractures of the large joints. Radiographically, the disease is characterized by a combination of decreased bone density, bowing of the long bones, platyspondyly and striking irregularities of endochondral ossification with areas of calcific stippling and streaking in radiolucent epiphyses, metaphyses and apophyses. The disease is caused by variants affecting the gene represented in this entry. Digital arthropathy-brachydactyly, familial (FDAB) [MIM:606835] A disorder characterized by irregularities in the proximal articular surfaces of the distal interphalangeal joints of the hand. Individuals appear normal at birth, with no clinical or radiographic evidence of a developmental skeletal dysplasia. The earliest changes appear during the first decade of life. By adulthood, all interphalangeal, metacarpophalangeal, and metatarsophalangeal joints are affected by a deforming, painful osteoarthritis. The remainder of the skeleton is clinically and radiographically unaffected. The disease is caused by variants affecting the gene represented in this entry. Avascular necrosis of the femoral head, primary 2 (ANFH2) [MIM:617383] A disease characterized by mechanical failure of the subchondral bone, and degeneration of the hip joint. It usually leads to destruction of the hip joint in the third to fifth decade of life. The clinical manifestations, such as pain on exertion, a limping gait, and a discrepancy in leg length, cause considerable disability. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Channel activation is inhibited by binding to phosphatidylinositol-4,5-bisphosphate, and to a much lesser degree by phosphatidylinositol-3,4,5-trisphosphate. Not inhibited by phosphatidylinositol-3,4-bisphosphate and phosphatidylinositol-3,5-bisphosphate.

Domain organisation. The ANK repeat region mediates interaction with Ca(2+)-calmodulin and ATP binding. The ANK repeat region mediates interaction with phosphatidylinositol-4,5-bisphosphate and related phosphatidylinositides.

Polymorphism. Genetic variations in TRPV4 determine the sodium serum level quantitative trait locus 1 (SSQTL1) [MIM:613508]. In some populations, variant Pro19Ser has been shown to be significantly associated with hyponatremia defined as serum sodium concentration below or equal to 135 mEq/L.

Miscellaneous. Lacks channel activity, due to impaired oligomerization and intracellular retention. Lacks channel activity, due to impaired oligomerization and intracellular retention. Forms active ion channels. Lacks channel activity, due to impaired oligomerization and intracellular retention.

Similarity. Belongs to the transient receptor (TC 1.A.4) family. TrpV subfamily. TRPV4 sub-subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
Q9HBA0-1	1, A	yes
Q9HBA0-2	2, B, OTRPC4beta
Q9HBA0-3	3, TRPV-SV
Q9HBA0-4	4, C
Q9HBA0-5	5, D
Q9HBA0-6	6, E

RefSeq proteins (5): NP_001170899, NP_001170902, NP_001170904, NP_067638, NP_671737 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR005821	Ion_trans_dom	Domain
IPR008347	TrpV1-4	Family
IPR008348	TrpV4	Family
IPR024862	TRPV	Family
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF00023, PF00520

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (163 total): sequence variant 44, helix 35, strand 20, mutagenesis site 10, binding site 9, topological domain 8, turn 8, transmembrane region 6, sequence conflict 6, modified residue 4, splice variant 4, repeat 3, region of interest 3, chain 1, intramembrane region 1, short sequence motif 1

Structure

Experimental structures (PDB)

19 structures.

PDB	Method	Resolution (Å)
8T1E	ELECTRON MICROSCOPY	2.77
4DX1	X-RAY DIFFRACTION	2.85
4DX2	X-RAY DIFFRACTION	2.95
8T1B	ELECTRON MICROSCOPY	3
9IQY	ELECTRON MICROSCOPY	3.16
8JVI	ELECTRON MICROSCOPY	3.21
8FC7	ELECTRON MICROSCOPY	3.3
8T1D	ELECTRON MICROSCOPY	3.35
9IQX	ELECTRON MICROSCOPY	3.37
8FCA	ELECTRON MICROSCOPY	3.41
8JVJ	ELECTRON MICROSCOPY	3.44
8JU6	ELECTRON MICROSCOPY	3.45
8FC8	ELECTRON MICROSCOPY	3.47
8T1C	ELECTRON MICROSCOPY	3.49
8T1F	ELECTRON MICROSCOPY	3.49
8FCB	ELECTRON MICROSCOPY	3.55
8JU5	ELECTRON MICROSCOPY	3.74
8FC9	ELECTRON MICROSCOPY	3.75
7AA5	ELECTRON MICROSCOPY	4.18

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HBA0-F1	72.06	0.22

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 (9): 192; 197; 201; 236–239; 248; 249–251; 296–299; 344; 682

Post-translational modifications (4): 110, 253, 805, 824

Mutagenesis-validated functional residues (10):

Position	Phenotype
231	decreased atp-binding.
251	no effect on channel activity. no effect on interaction with membranes enriched in phosphatidylinositol-2,4-bisphosphate
296	loss of interaction with membranes enriched in phosphatidylinositol-2,4-bisphosphate; when associated with p-299.
299	strongly decreased interaction with membranes enriched in phosphatidylinositol-2,4-bisphosphate. loss of interaction wit
344	no effect on channel activity. no effect on interaction with membranes enriched in phosphatidylinositol-2,4-bisphosphate
680	loss of ca(2+) influx. loss of ddx3x translocation to the nucleus.
816–821	loss of calmodulin binding; when associated with a-828.
821–824	loss of calmodulin binding.
822	loss of ca(2+) dependent current potentiation.
828	loss of calmodulin binding; when associated with 816-eleede-821.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3295583	TRP channels
R-HSA-9856530	High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells

MSigDB gene sets: 736 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_CYTOPLASMIC_MICROTUBULE_ORGANIZATION, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CARTILAGE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_INFLAMMATORY_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_DIETARY_EXCESS, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_HORMONE_LEVELS, GOCC_CELL_SURFACE

GO Biological Process (52): negative regulation of transcription by RNA polymerase II (GO:0000122), response to hypoxia (GO:0001666), diet induced thermogenesis (GO:0002024), calcium ion transport (GO:0006816), intracellular calcium ion homeostasis (GO:0006874), cell volume homeostasis (GO:0006884), actin filament organization (GO:0007015), cell-cell junction assembly (GO:0007043), positive regulation of cytosolic calcium ion concentration (GO:0007204), osmosensory signaling pathway (GO:0007231), response to mechanical stimulus (GO:0009612), positive regulation of macrophage chemotaxis (GO:0010759), negative regulation of neuron projection development (GO:0010977), actin cytoskeleton organization (GO:0030036), vasopressin secretion (GO:0030103), positive regulation of microtubule depolymerization (GO:0031117), positive regulation of interleukin-6 production (GO:0032755), response to insulin (GO:0032868), cellular response to heat (GO:0034605), hyperosmotic salinity response (GO:0042538), glucose homeostasis (GO:0042593), positive regulation of vascular permeability (GO:0043117), cortical microtubule organization (GO:0043622), positive regulation of striated muscle contraction (GO:0045989), positive regulation of JNK cascade (GO:0046330), microtubule polymerization (GO:0046785), regulation of response to osmotic stress (GO:0047484), positive regulation of inflammatory response (GO:0050729), multicellular organismal-level water homeostasis (GO:0050891), cartilage development involved in endochondral bone morphogenesis (GO:0060351), positive regulation of ERK1 and ERK2 cascade (GO:0070374), calcium ion import (GO:0070509), calcium ion transmembrane transport (GO:0070588), cellular response to osmotic stress (GO:0071470), cellular hypotonic response (GO:0071476), cellular hypotonic salinity response (GO:0071477), positive regulation of monocyte chemotactic protein-1 production (GO:0071639), positive regulation of macrophage inflammatory protein 1 alpha production (GO:0071642), positive regulation of chemokine (C-C motif) ligand 5 production (GO:0071651), blood vessel endothelial cell delamination (GO:0097497)

GO Molecular Function (20): actin binding (GO:0003779), osmosensor activity (GO:0005034), protein kinase C binding (GO:0005080), monoatomic cation channel activity (GO:0005261), calcium channel activity (GO:0005262), calmodulin binding (GO:0005516), ATP binding (GO:0005524), microtubule binding (GO:0008017), lipid binding (GO:0008289), stretch-activated, monoatomic cation-selective, calcium channel activity (GO:0015275), protein kinase binding (GO:0019901), SH2 domain binding (GO:0042169), identical protein binding (GO:0042802), alpha-tubulin binding (GO:0043014), metal ion binding (GO:0046872), beta-tubulin binding (GO:0048487), actin filament binding (GO:0051015), nucleotide binding (GO:0000166), monoatomic ion channel activity (GO:0005216), protein binding (GO:0005515)

GO Cellular Component (16): endoplasmic reticulum (GO:0005783), cytoplasmic microtubule (GO:0005881), plasma membrane (GO:0005886), adherens junction (GO:0005912), focal adhesion (GO:0005925), cilium (GO:0005929), cell surface (GO:0009986), membrane (GO:0016020), apical plasma membrane (GO:0016324), lamellipodium (GO:0030027), filopodium (GO:0030175), growth cone (GO:0030426), cortical actin cytoskeleton (GO:0030864), ruffle membrane (GO:0032587), cell projection (GO:0042995), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Stimuli-sensing channels	1
Response of endothelial cells to shear stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
tubulin binding	3
cellular anatomical structure	3
protein binding	2
binding	2
cytoplasm	2
plasma membrane bounded cell projection	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
response to stress	1
response to decreased oxygen levels	1
response to dietary excess	1
adaptive thermogenesis	1
metal ion transport	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
regulation of cell size	1
cellular homeostasis	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
cell junction assembly	1
cell-cell junction organization	1
regulation of biological quality	1
intracellular signal transduction	1
cellular response to osmotic stress	1
response to external stimulus	1
response to abiotic stimulus	1
positive regulation of leukocyte chemotaxis	1
regulation of macrophage chemotaxis	1
macrophage chemotaxis	1
regulation of granulocyte chemotaxis	1
positive regulation of macrophage migration	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
cytoskeleton organization	1
actin filament-based process	1
peptide hormone secretion	1
microtubule depolymerization	1
positive regulation of microtubule polymerization or depolymerization	1

Protein interactions and networks

STRING

1816 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRPV4	TRPC1	P48995	996
TRPV4	PKD2	Q13563	974
TRPV4	CAV1	Q03135	945
TRPV4	TRPC6	Q9Y210	941
TRPV4	TRPM8	Q7Z2W7	889
TRPV4	PKD1	P98161	870
TRPV4	CALML3	P27482	868
TRPV4	CALML5	Q9NZT1	868
TRPV4	TRPC4	Q9UBN4	867
TRPV4	CALML4	Q96GE6	866
TRPV4	CALML6	Q8TD86	865
TRPV4	AQP5	P55064	854
TRPV4	TRPM4	Q8TD43	844
TRPV4	ANK1	P16157	810
TRPV4	PACSIN3	Q9UKS6	802

IntAct

21 interactions, top by confidence:

A	B	Type	Score
B4GAT1	ADCY6	psi-mi:“MI:0914”(association)	0.530
TRPV4	TRPV4	psi-mi:“MI:0915”(physical association)	0.470
TRPV4	TRPV4	psi-mi:“MI:2364”(proximity)	0.470
HIF1AN	TRPV4	psi-mi:“MI:0210”(hydroxylation reaction)	0.440
Aqp4	TRPV4	psi-mi:“MI:0915”(physical association)	0.400
TRPV4	Agtr1	psi-mi:“MI:0915”(physical association)	0.400
TRPV4	RAN	psi-mi:“MI:0915”(physical association)	0.400
	AQP4	psi-mi:“MI:0914”(association)	0.350
	HEPACAM	psi-mi:“MI:0914”(association)	0.350
E5	ESYT2	psi-mi:“MI:0914”(association)	0.350
ARRB2		psi-mi:“MI:0914”(association)	0.350
PACSIN1	WASL	psi-mi:“MI:0914”(association)	0.350
S1PR3	STXBP3	psi-mi:“MI:0914”(association)	0.350
ZDHHC11	NRP1	psi-mi:“MI:0914”(association)	0.350
CANX	TRPV4	psi-mi:“MI:0403”(colocalization)	0.270

BioGRID (111): AKAP5 (Affinity Capture-Western), TRPV4 (Affinity Capture-Western), TRPV4 (Reconstituted Complex), MAP7 (Affinity Capture-Western), MAP7 (Two-hybrid), TRPV4 (Affinity Capture-MS), TRPV4 (Biochemical Activity), SRC (Affinity Capture-Western), LYN (Affinity Capture-Western), YES1 (Affinity Capture-Western), LCK (Affinity Capture-Western), HCK (Affinity Capture-Western), FYN (Affinity Capture-Western), TRPV4 (Affinity Capture-Western), OS9 (Affinity Capture-Western)

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: A0A1D5PXA5, O35433, P69744, Q697L1, Q6R5A3, Q6RX08, Q704Y3, Q8K424, Q8NER1, Q8NET8, Q91WD2, Q9EPK8, Q9ERZ8, Q9H1D0, Q9HBA0, Q9JIP0, Q9NQA5, Q9R186, Q9WTR1, Q9WUD2, Q9XSM3, Q9Y5S1, Q810B6, Q9P2R3, P83757, Q03017

SIGNOR signaling

19 interactions.

A	Effect	B	Mechanism
PKA	“up-regulates activity”	TRPV4	phosphorylation
PRKCA	“up-regulates activity”	TRPV4	phosphorylation
OS9	“up-regulates quantity by stabilization”	TRPV4	binding
ITCH	“down-regulates activity”	TRPV4	ubiquitination
SGK1	“up-regulates activity”	TRPV4	phosphorylation
FYN	“up-regulates activity”	TRPV4	phosphorylation
TRPV4	“down-regulates quantity by repression”	PPARGC1A	“transcriptional regulation”
TRPV4	“down-regulates quantity by repression”	UCP1	“transcriptional regulation”
GSK1016790A	“up-regulates activity”	TRPV4	binding
PKC	“up-regulates activity”	TRPV4	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1323 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	26
Uncertain significance	648
Likely benign	378
Benign	57

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1045051	NM_021625.5(TRPV4):c.838G>A (p.Gly280Ser)	Pathogenic
1073853	NM_021625.5(TRPV4):c.709C>G (p.Arg237Gly)	Pathogenic
126463	NM_021625.5(TRPV4):c.1219A>G (p.Lys407Glu)	Pathogenic
126473	NM_021625.5(TRPV4):c.1853T>C (p.Leu618Pro)	Pathogenic
126478	NM_021625.5(TRPV4):c.2396_2412del (p.Pro799fs)	Pathogenic
126483	NM_021625.5(TRPV4):c.819C>G (p.Phe273Leu)	Pathogenic
1328137	NM_021625.5(TRPV4):c.245C>T (p.Pro82Leu)	Pathogenic
1453327	NM_021625.5(TRPV4):c.1849T>C (p.Phe617Leu)	Pathogenic
1458308	NM_021625.5(TRPV4):c.1799G>A (p.Gly600Glu)	Pathogenic
18430	NM_021625.5(TRPV4):c.2395C>G (p.Pro799Ala)	Pathogenic
18431	NM_021625.5(TRPV4):c.2395C>T (p.Pro799Ser)	Pathogenic
18434	NM_021625.5(TRPV4):c.832G>A (p.Glu278Lys)	Pathogenic
18435	NM_021625.5(TRPV4):c.2389G>A (p.Glu797Lys)	Pathogenic
234619	NM_021625.5(TRPV4):c.290C>G (p.Pro97Arg)	Pathogenic
2780255	NM_021625.5(TRPV4):c.1058G>A (p.Cys353Tyr)	Pathogenic
30468	NM_021625.5(TRPV4):c.1805A>G (p.Tyr602Cys)	Pathogenic
30469	NM_021625.5(TRPV4):c.1625C>A (p.Ser542Tyr)	Pathogenic
30470	NM_021625.5(TRPV4):c.266C>T (p.Thr89Ile)	Pathogenic
30472	NM_021625.5(TRPV4):c.694C>T (p.Arg232Cys)	Pathogenic
30474	NM_021625.5(TRPV4):c.232G>T (p.Gly78Trp)	Pathogenic
30475	NM_021625.5(TRPV4):c.2219C>T (p.Thr740Ile)	Pathogenic
30476	NM_021625.5(TRPV4):c.826A>G (p.Lys276Glu)	Pathogenic
35512	NM_021625.5(TRPV4):c.812G>C (p.Arg271Pro)	Pathogenic
35513	NM_021625.5(TRPV4):c.809G>T (p.Gly270Val)	Pathogenic
370071	NM_021625.5(TRPV4):c.1207T>A (p.Ser403Thr)	Pathogenic
4992	NM_021625.5(TRPV4):c.1847G>A (p.Arg616Gln)	Pathogenic
4995	NM_021625.5(TRPV4):c.998A>G (p.Asp333Gly)	Pathogenic
4997	NM_021625.5(TRPV4):c.991A>T (p.Ile331Phe)	Pathogenic
4998	NM_021625.5(TRPV4):c.2396C>T (p.Pro799Leu)	Pathogenic
5001	NM_021625.5(TRPV4):c.946C>T (p.Arg316Cys)	Pathogenic

SpliceAI

2322 predictions. Top by Δscore:

Variant	Effect	Δscore
12:109783785:C:CT	acceptor_gain	1.0000
12:109783786:G:T	acceptor_gain	1.0000
12:109784314:ACC:A	donor_gain	1.0000
12:109784315:CCC:C	donor_gain	1.0000
12:109784433:CCACC:C	acceptor_gain	1.0000
12:109784434:CACCC:C	acceptor_gain	1.0000
12:109784436:CC:C	acceptor_gain	1.0000
12:109784437:CC:C	acceptor_gain	1.0000
12:109784438:C:CC	acceptor_gain	1.0000
12:109784449:C:CT	acceptor_gain	1.0000
12:109784449:C:T	acceptor_gain	1.0000
12:109784450:A:T	acceptor_gain	1.0000
12:109786833:GCCCA:G	acceptor_gain	1.0000
12:109786834:CCCA:C	acceptor_gain	1.0000
12:109786834:CCCAC:C	acceptor_gain	1.0000
12:109786835:CCA:C	acceptor_gain	1.0000
12:109786835:CCAC:C	acceptor_gain	1.0000
12:109786836:CA:C	acceptor_gain	1.0000
12:109786836:CAC:C	acceptor_gain	1.0000
12:109786838:C:CC	acceptor_gain	1.0000
12:109788394:CCTCA:C	donor_loss	1.0000
12:109788395:CTCAC:C	donor_loss	1.0000
12:109788396:TCACC:T	donor_loss	1.0000
12:109788397:CACC:C	donor_loss	1.0000
12:109788399:C:CA	donor_loss	1.0000
12:109788712:CAGGG:C	acceptor_gain	1.0000
12:109788714:GGG:G	acceptor_gain	1.0000
12:109788717:C:CC	acceptor_gain	1.0000
12:109792441:A:T	acceptor_gain	1.0000
12:109792448:T:TC	acceptor_gain	1.0000

AlphaMissense

5702 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:109784410:C:A	W788C	1.000
12:109784410:C:G	W788C	1.000
12:109784412:A:G	W788R	1.000
12:109784412:A:T	W788R	1.000
12:109784419:C:A	W785C	1.000
12:109784419:C:G	W785C	1.000
12:109784421:A:G	W785R	1.000
12:109784421:A:T	W785R	1.000
12:109786721:C:A	R775S	1.000
12:109786721:C:G	R775S	1.000
12:109786722:C:A	R775M	1.000
12:109788454:C:A	M718I	1.000
12:109788454:C:G	M718I	1.000
12:109788454:C:T	M718I	1.000
12:109788458:A:G	L717P	1.000
12:109788464:A:T	I715N	1.000
12:109788467:A:G	L714P	1.000
12:109788472:G:C	N712K	1.000
12:109788472:G:T	N712K	1.000
12:109788476:A:G	L711P	1.000
12:109788482:A:G	L709P	1.000
12:109792374:C:T	G627D	1.000
12:109792403:G:C	F617L	1.000
12:109792403:G:T	F617L	1.000
12:109792404:A:G	F617S	1.000
12:109792405:A:G	F617L	1.000
12:109792677:C:T	G600E	1.000
12:109794459:G:T	P454H	1.000
12:109796619:G:T	P413Q	1.000
12:109796622:C:A	G412V	1.000

dbSNP variants (sampled 300 via entrez): RS1000006350 (12:109827346 G>A), RS1000009788 (12:109824156 G>A), RS1000108712 (12:109830459 A>C), RS1000119636 (12:109818271 G>C), RS1000270022 (12:109783428 G>C,T), RS1000312650 (12:109834064 A>G), RS1000392808 (12:109786500 T>C), RS1000423120 (12:109828109 T>C), RS1000481856 (12:109812235 C>T), RS1000506967 (12:109820194 A>C), RS1000518437 (12:109789159 G>A), RS1000599284 (12:109820996 C>T), RS1000602737 (12:109784437 C>A), RS1000648757 (12:109832927 C>T), RS1000700247 (12:109813922 A>C)

Disease associations

OMIM: gene MIM:605427 | disease phenotypes: MIM:606071, MIM:113500, MIM:156530, MIM:168400, MIM:181405, MIM:184095, MIM:184252, MIM:600175, MIM:606835, MIM:617383, MIM:602613, MIM:118220, MIM:182960, MIM:160500, MIM:609129, MIM:119800, MIM:132400, MIM:602099, MIM:616668, MIM:117000

GenCC curated gene-disease

Disease	Classification	Inheritance
TRPV4-related bone disorder	Definitive	Autosomal dominant
metatropic dysplasia	Definitive	Autosomal dominant
spondylometaphyseal dysplasia, Kozlowski type	Definitive	Autosomal dominant
autosomal dominant brachyolmia	Strong	Autosomal dominant
Charcot-Marie-Tooth disease axonal type 2C	Strong	Autosomal dominant
neuromuscular disease	Strong	Autosomal dominant
scapuloperoneal spinal muscular atrophy, autosomal dominant	Moderate	Autosomal dominant
neuronopathy, distal hereditary motor, autosomal dominant 8	Supportive	Autosomal dominant
parastremmatic dwarfism	Supportive	Autosomal dominant
familial digital arthropathy-brachydactyly	Supportive	Autosomal dominant
familial avascular necrosis of femoral head	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
TRPV4-related bone disorder	Definitive	AD
neuromuscular disease	Definitive	AD

Mondo (30): Charcot-Marie-Tooth disease axonal type 2C (MONDO:0011633), autosomal dominant brachyolmia (MONDO:0007232), metatropic dysplasia (MONDO:0007986), parastremmatic dwarfism (MONDO:0008196), scapuloperoneal spinal muscular atrophy, autosomal dominant (MONDO:0008408), spondyloepimetaphyseal dysplasia, Maroteaux type (MONDO:0008473), spondylometaphyseal dysplasia, Kozlowski type (MONDO:0008477), neuronopathy, distal hereditary motor, autosomal dominant 8 (MONDO:0010839), familial digital arthropathy-brachydactyly (MONDO:0011732), avascular necrosis of femoral head, primary, 2 (MONDO:0054551), TRPV4-related bone disorder (MONDO:0018240), skeletal dysplasia (MONDO:0018230), skeletal dysplasia and progressive central nervous system degeneration, lethal (MONDO:0011263), Charcot-Marie-Tooth disease (MONDO:0015626), neuromuscular disease (MONDO:0019056)

Orphanet (24): Autosomal dominant Charcot-Marie-Tooth disease type 2C (Orphanet:99937), Autosomal dominant congenital benign spinal muscular atrophy (Orphanet:1216), Spondyloepimetaphyseal dysplasia, Maroteaux type (Orphanet:263482), Metatropic dysplasia (Orphanet:2635), Parastremmatic dysplasia (Orphanet:2646), Scapuloperoneal spinal muscular atrophy (Orphanet:431255), Familial digital arthropathy-brachydactyly (Orphanet:85169), Autosomal dominant brachyolmia (Orphanet:93304), Spondylometaphyseal dysplasia, Kozlowski type (Orphanet:93314), TRPV4-related bone disorder (Orphanet:364820), Primary bone dysplasia (Orphanet:364526), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Neuromuscular disease (Orphanet:68381), Autosomal dominant distal hereditary motor neuropathy (Orphanet:140465), Distal hereditary motor neuropathy (Orphanet:53739)

HPO phenotypes

214 total (30 of 214 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000012	Urinary urgency
HP:0000020	Urinary incontinence
HP:0000175	Cleft palate
HP:0000238	Hydrocephalus
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000407	Sensorineural hearing impairment
HP:0000470	Short neck
HP:0000473	Torticollis
HP:0000518	Cataract
HP:0000540	Hypermetropia
HP:0000763	Sensory neuropathy
HP:0000768	Pectus carinatum
HP:0000772	Abnormal rib morphology
HP:0000773	Short ribs
HP:0000774	Narrow chest
HP:0000887	Cupped ribs
HP:0000904	Flaring of rib cage
HP:0000914	Shield chest
HP:0000925	Abnormality of the vertebral column
HP:0000926	Platyspondyly
HP:0000944	Abnormal metaphysis morphology
HP:0001156	Brachydactyly
HP:0001216	Delayed ossification of carpal bones
HP:0001248	Short tubular bones of the hand
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001265	Hyporeflexia
HP:0001270	Motor delay

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST005984_60	Glomerular filtration rate	5.000000e-09
GCST005985_39	Creatinine levels	3.000000e-09
GCST011946_24	White matter hyperintensity volume	9.000000e-06
GCST011947_8	White matter hyperintensity volume	4.000000e-06
GCST011949_41	White matter hyperintensity volume (adjusted for hypertension)	9.000000e-06
GCST011950_23	White matter hyperintensity volume (adjusted for hypertension)	5.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005665	white matter hyperintensity measurement

MeSH disease descriptors (14)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D003025	Clubfoot	C05.330.488.655.063; C05.330.495.681.063; C05.660.585.512.380.813.063; C16.131.621.585.512.500.681.063
D003240	Connective Tissue Diseases	C17.300
D005271	Femur Head Necrosis	C05.116.852.175; C23.550.717.732.368
D009208	Myoepithelioma	C04.557.435.585
D009468	Neuromuscular Diseases	C10.668
C566576	Amyotrophic Lateral Sclerosis 5 (supp.)
C538268	Auditory neuropathy (supp.)
C564656	Digital Arthropathy-Brachydactyly, Familial (supp.)
C537356	Metatropic dwarfism (supp.)
C537172	Parastremmatic dwarfism (supp.)
C566514	Skeletal Dysplasia And Progressive Central Nervous System Degeneration, Lethal (supp.)
C563981	Spinal Muscular Atrophy, Distal, Congenital Nonprogressive (supp.)
C535797	Spondylometaphyseal dysplasia, Kozlowski type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3119 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 39,916 (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
CHEMBL74415	CANNABINOL	3	18,794
CHEMBL2387541	TETRAHYDROCANNABIVARIN	2	4,884
CHEMBL2387742	CANNABIDIVARIN	2	4,963
CHEMBL4470585	GSK2798745	2	57
CHEMBL497318	CANNABIGEROL	2	11,097
CHEMBL398338	ABT-102	1	121

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 (26 total), top 25:

Ligand	Action	Affinity	Parameter
GSK2798745	Inhibition	8.82	pIC50
GSK1016790A	Activation	8.7	pEC50
phorbol 12-myristate 13-acetate	Agonist	7.9	pEC50
GSK-Bz derivative 2b	Inhibition	7.66	pIC50
GSK2193874	Inhibition	7.4	pEC50
HC067047	Inhibition	7.3	pIC50
quinazolin-4(3H) derivative 36	Activation	7.22	pEC50
NSC212069	Inhibition	7.16	pIC50
4α-PDH	Activation	7.1	pEC50
5,6-epoxyeicosatrienoic acid	Agonist	6.9	pEC50
NSC151066	Inhibition	6.84	pIC50
paracetamol	Inhibition	6.52	pIC50
4α-PDD	Agonist	6.5	pEC50
NSC600684	Inhibition	6.44	pIC50
RN-9893	Antagonist	6.2	pIC50
RN1747	Activation	6.1	pEC50
bisandrographolide	Agonist	6.0	pEC50
cimifugin	Inhibition	5.8	pIC50
citric acid	Agonist	5.6	pEC50
RN1734	Inhibition	5.6	pIC50
curcumin	Activation	5.18	pEC50
AM404	Inhibition	5.0	pIC50
arachidonic acid	Activation	5.0	pEC50
puerarin	Activation	4.77	pEC50
propofol	Inhibition	4.41	pIC50

Binding affinities (BindingDB)

228 measured of 228 human assays (228 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[4-[3,5-dichloro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	1.45 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	1.68 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(1,3-dimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)-N-[4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	2.15 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(1,3-dimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)-N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	2.21 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-4a,7a-dihydrothieno[2,3-d]pyrimidin-5-yl)acetamide	IC50	2.49 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	2.93 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[4-chloro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	3.18 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3,5-dichloro-4-(2-methylpropoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	3.34 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3,5-difluoro-4-(3,3,3-trifluoropropyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	3.38 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3-chloro-5-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	3.54 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[4-(2,2-dimethylpropoxy)-3,5-difluorophenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	3.63 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl]-2-(6-ethyl-1,3-dimethyl-2,4-dioxo-4a,7a-dihydrothieno[2,3-d]pyrimidin-5-yl)acetamide	IC50	3.98 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	4.02 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3,5-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	4.16 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(5,7-dimethyl-4,6-dioxo-2,3,3a,7a-tetrahydro-[1,2]thiazolo[5,4-d]pyrimidin-3-yl)-N-[4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	4.4 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	4.52 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[4-fluoro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	4.84 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(6-chloro-1,3-dimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)-N-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	5.06 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(6-chloro-1,3-dimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)-N-[4-[3-fluoro-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	5.15 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3-chloro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	5.29 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(5,7-dimethyl-4,6-dioxo-2,3,3a,7a-tetrahydro-[1,2]thiazolo[5,4-d]pyrimidin-3-yl)-N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	5.29 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-2,3,3a,7a-tetrahydro-[1,2]thiazolo[5,4-d]pyrimidin-3-yl)acetamide	IC50	5.35 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3,5-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-4aH-quinazolin-1-ium-5-yl)acetamide	IC50	5.37 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-2,3,3a,7a-tetrahydro-[1,2]thiazolo[5,4-d]pyrimidin-3-yl)acetamide	IC50	5.6 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
4-[3-(3-methoxypropoxy)phenyl]-2-sulfanylidene-3,4-dihydro-1H-indeno[1,2-d]pyrimidin-5-one	IC50	5.61 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-4aH-quinazolin-1-ium-5-yl)acetamide	IC50	5.96 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3-chloro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]-2-(5,7-dimethyl-4,6-dioxo-2,3,3a,7a-tetrahydro-[1,2]thiazolo[5,4-d]pyrimidin-3-yl)acetamide	IC50	6.28 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-4aH-quinazolin-1-ium-5-yl)acetamide	IC50	6.49 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	6.65 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(5,7-dimethyl-4,6-dioxo-2,3,3a,7a-tetrahydro-[1,2]thiazolo[5,4-d]pyrimidin-3-yl)-N-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	6.74 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3,5-difluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3-dimethyl-2,4-dioxo-4aH-pyrido[2,3-d]pyrimidin-1-ium-5-yl)acetamide	IC50	6.91 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	7.1 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(6-chloro-1,3-dimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)-N-[4-[2,3-difluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	7.58 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(6-chloro-1,3-dimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)-N-[4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	7.67 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(5,7-dimethyl-4,6-dioxo-2,3,3a,7a-tetrahydro-[1,2]thiazolo[5,4-d]pyrimidin-3-yl)-N-[4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	8.04 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3-chloro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	8.54 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(1,3-dimethyl-2,4-dioxo-4aH-pyrido[2,3-d]pyrimidin-1-ium-5-yl)-N-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	8.92 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[4-chloro-3-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	9.04 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(6-chloro-1,3-dimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)-N-[4-[2,4-difluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	10.1 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(5,7-dimethyl-4,6-dioxo-2,3,3a,7a-tetrahydro-[1,2]thiazolo[5,4-d]pyrimidin-3-yl)-N-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	10.6 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]-2-(2,5,7-trimethyl-4,6-dioxo-1,7a-dihydropyrazolo[3,4-d]pyrimidin-3-yl)acetamide	IC50	11 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(1,3-dimethyl-2,4-dioxo-4aH-quinazolin-1-ium-5-yl)-N-[4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	11.4 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
US9186360, 42	IC50	11.4 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(1,3-dimethyl-2,4-dioxo-4aH-pyrido[2,3-d]pyrimidin-1-ium-5-yl)-N-[4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	11.4 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(1,3-dimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)-N-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	11.9 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3,5-dichloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl]-2-(4,6-dimethyl-5,7-dioxo-7aH-pyrazolo[4,3-d]pyrimidin-4-ium-1-yl)acetamide	IC50	12.3 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3-fluoro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	12.6 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
2-(1,3-dimethyl-2,4-dioxo-4aH-quinazolin-1-ium-5-yl)-N-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]acetamide	IC50	13.4 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[2-fluoro-3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-4a,7a-dihydrofuro[2,3-d]pyrimidin-5-yl)acetamide	IC50	13.6 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists
N-[4-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]-2-(2,5,7-trimethyl-4,6-dioxo-1,7a-dihydropyrazolo[3,4-d]pyrimidin-3-yl)acetamide	IC50	15.9 nM	US-9186360: Treatment of respiratory disorders using TRPA1 antagonists

ChEMBL bioactivities

736 potent at pChembl≥5 of 745 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.74	IC50	0.18	nM	CHEMBL4096902
9.72	IC50	0.19	nM	CHEMBL4101768
9.68	IC50	0.21	nM	CHEMBL4066531
9.66	IC50	0.22	nM	CHEMBL3941914
9.54	IC50	0.29	nM	CHEMBL4099293
9.52	IC50	0.3	nM	CHEMBL3971502
9.52	IC50	0.3	nM	CHEMBL4456312
9.51	IC50	0.31	nM	CHEMBL4077638
9.44	IC50	0.36	nM	CHEMBL3984947
9.41	IC50	0.39	nM	CHEMBL4078117
9.40	IC50	0.4	nM	CHEMBL3941914
9.30	IC50	0.5	nM	CHEMBL4095552
9.30	IC50	0.5	nM	CHEMBL4469630
9.30	IC50	0.5	nM	CHEMBL4547537
9.30	IC50	0.5	nM	CHEMBL4461475
9.24	IC50	0.57	nM	CHEMBL3933401
9.21	IC50	0.62	nM	CHEMBL4060956
9.19	IC50	0.65	nM	CHEMBL4062935
9.15	IC50	0.71	nM	CHEMBL4090714
9.07	IC50	0.85	nM	CHEMBL4459940
9.06	IC50	0.87	nM	CHEMBL4084992
9.05	IC50	0.9	nM	CHEMBL3950646
9.01	IC50	0.97	nM	CHEMBL4083772
9.00	IC50	1	nM	CHEMBL3915150
9.00	IC50	0.99	nM	CHEMBL4091558
9.00	IC50	1	nM	CHEMBL4168219
9.00	IC50	1	nM	ABT-102
8.96	IC50	1.1	nM	CHEMBL3957347
8.92	IC50	1.2	nM	CHEMBL4521512
8.92	IC50	1.2	nM	CHEMBL4588831
8.92	IC50	1.2	nM	CHEMBL4578182
8.90	IC50	1.259	nM	CHEMBL4749555
8.89	IC50	1.3	nM	CHEMBL4080527
8.89	IC50	1.3	nM	CHEMBL4069724
8.85	IC50	1.4	nM	CHEMBL4083195
8.82	IC50	1.5	nM	CHEMBL4536058
8.80	IC50	1.6	nM	CHEMBL4532369
8.77	IC50	1.7	nM	CHEMBL3924485
8.77	IC50	1.7	nM	CHEMBL4541827
8.74	IC50	1.8	nM	CHEMBL3985107
8.74	IC50	1.8	nM	CHEMBL4077429
8.74	IC50	1.8	nM	GSK2798745
8.72	IC50	1.9	nM	CHEMBL3985405
8.72	IC50	1.9	nM	CHEMBL4460657
8.70	IC50	2	nM	CHEMBL4063752
8.70	IC50	2	nM	CHEMBL4439448
8.70	IC50	2	nM	CHEMBL4586959
8.70	IC50	2	nM	GSK2798745
8.68	IC50	2.1	nM	CHEMBL3979114
8.66	IC50	2.2	nM	CHEMBL4083195

PubChem BioAssay actives

361 with measured affinity, of 523 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
3-[[(5S,7S)-3-[(3-bromophenyl)methyl]-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl]methyl]benzimidazole-5-carbonitrile	726058: Antagonist activity at TRPV4 (unknown origin) by ligand-gated assay	ic50	<0.0001	uM
3-[[(5S,7R)-7-(cyanomethyl)-3-[(4-methoxyphenyl)methyl]-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl]methyl]benzimidazole-5-carbonitrile	726058: Antagonist activity at TRPV4 (unknown origin) by ligand-gated assay	ic50	<0.0001	uM
3-[[(5S,7S)-3-[(2-fluorophenyl)methyl]-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl]methyl]benzimidazole-5-carbonitrile	726058: Antagonist activity at TRPV4 (unknown origin) by ligand-gated assay	ic50	<0.0001	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[3-[5-(trifluoromethyl)pyrimidin-2-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone	1316747: Antagonist activity at human TRPV4 assessed as inhibition of 4alpha-PDD-induced activation	ic50	0.0002	uM
[3-(5-bromopyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]methanone	1481466: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of 4alphaPDD-induced activation pretreated for 5 mins followed by 4alphaPDD stimulation measured for 5 mins by FLIPR assay	ic50	0.0002	uM
2-[8-[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]pyridine-3-carbonyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyrimidine-5-carbonitrile	1481466: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of 4alphaPDD-induced activation pretreated for 5 mins followed by 4alphaPDD stimulation measured for 5 mins by FLIPR assay	ic50	0.0002	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[7-[5-(trifluoromethyl)pyrimidin-2-yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl]methanone	1481466: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of 4alphaPDD-induced activation pretreated for 5 mins followed by 4alphaPDD stimulation measured for 5 mins by FLIPR assay	ic50	0.0002	uM
[3-(5-chloropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]methanone	1316747: Antagonist activity at human TRPV4 assessed as inhibition of 4alpha-PDD-induced activation	ic50	0.0003	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[3-(5-fluoropyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone	1481466: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of 4alphaPDD-induced activation pretreated for 5 mins followed by 4alphaPDD stimulation measured for 5 mins by FLIPR assay	ic50	0.0003	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[2-(trifluoromethyl)-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]methanone	1481466: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of 4alphaPDD-induced activation pretreated for 5 mins followed by 4alphaPDD stimulation measured for 5 mins by FLIPR assay	ic50	0.0003	uM
4-[(3S,4S)-3-(aminomethyl)-4-(4-chlorophenyl)sulfonyl-3-hydroxypyrrolidin-1-yl]sulfonyl-3-chlorobenzonitrile	1586307: Antagonist activity at human TRPV4 expressed in BHK/AC9 cells assessed as inhibition of GSK634775-induced calcium immobilization pre-incubated for 10 mins followed by agonist addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0003	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[(1R,5S)-3-(2,2,2-trifluoroethoxyimino)-8-azabicyclo[3.2.1]octan-8-yl]methanone	1316747: Antagonist activity at human TRPV4 assessed as inhibition of 4alpha-PDD-induced activation	ic50	0.0004	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[3-(5-methylsulfonylpyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone	1481466: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of 4alphaPDD-induced activation pretreated for 5 mins followed by 4alphaPDD stimulation measured for 5 mins by FLIPR assay	ic50	0.0004	uM
4-[(3S,4S)-3-(aminomethyl)-4-[(5-chloro-2-pyridinyl)sulfonyl]-3-hydroxypyrrolidin-1-yl]sulfonyl-3-chlorobenzonitrile	1586307: Antagonist activity at human TRPV4 expressed in BHK/AC9 cells assessed as inhibition of GSK634775-induced calcium immobilization pre-incubated for 10 mins followed by agonist addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0005	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-(3-pyrimidin-2-yl-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone	1481466: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of 4alphaPDD-induced activation pretreated for 5 mins followed by 4alphaPDD stimulation measured for 5 mins by FLIPR assay	ic50	0.0005	uM
4-[(3R,4S)-3-(aminomethyl)-4-[(5-chloro-2-pyridinyl)sulfonyl]-3-hydroxypyrrolidin-1-yl]sulfonyl-3-chlorobenzonitrile	1586307: Antagonist activity at human TRPV4 expressed in BHK/AC9 cells assessed as inhibition of GSK634775-induced calcium immobilization pre-incubated for 10 mins followed by agonist addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0005	uM
3-[[(5S,7S)-3-(2,2-dimethylpropyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl]methyl]benzimidazole-5-carbonitrile	1511301: Inhibition of human TRPV4 expressed in baculovirus infected HEK/MSR 2 cells pre-incubated for 10 mins followed by GSK634775A addition by Fura-2 dye based FLIPR assay	ic50	0.0005	uM
methyl 4-[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]pyridine-3-carbonyl]-3-(trifluoromethyl)piperazine-1-carboxylate	1316747: Antagonist activity at human TRPV4 assessed as inhibition of 4alpha-PDD-induced activation	ic50	0.0006	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[3-[5-(hydroxymethyl)pyrimidin-2-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone	1481466: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of 4alphaPDD-induced activation pretreated for 5 mins followed by 4alphaPDD stimulation measured for 5 mins by FLIPR assay	ic50	0.0006	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[(2S)-2-methyl-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]methanone	1481466: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of 4alphaPDD-induced activation pretreated for 5 mins followed by 4alphaPDD stimulation measured for 5 mins by FLIPR assay	ic50	0.0006	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[3-[5-(trifluoromethyl)pyrazin-2-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone	1481467: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of hypotonicity-induced activation pretreated for 5 mins followed by hypotonic solution addition measured for 5 mins by FLIPR assay	ic50	0.0007	uM
N-[4-cyclobutyl-5-(2-piperidin-1-ylethyl)-1,3-thiazol-2-yl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide;dihydrochloride	1588942: Inhibition of human TRPV4 expressed in HEK293 cells assessed as reduction in Ca2+ influx incubated for 30 mins by Fluo4-AM dye based	ic50	0.0008	uM
[3-(5-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]methanone	1316747: Antagonist activity at human TRPV4 assessed as inhibition of 4alpha-PDD-induced activation	ic50	0.0009	uM
[6-[[4-(1,3-dimethylpyrazol-4-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[3-[5-(trifluoromethyl)pyrimidin-2-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone	1481466: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of 4alphaPDD-induced activation pretreated for 5 mins followed by 4alphaPDD stimulation measured for 5 mins by FLIPR assay	ic50	0.0009	uM
1-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-3-(1H-indazol-4-yl)urea	2032635: Antagonist activity at TRPV4 (unknown origin) assessed as inhibition of capsaicin induced Ca2+ influx	ic50	0.0010	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[(1R,5S)-3-methoxyimino-8-azabicyclo[3.2.1]octan-8-yl]methanone	1316747: Antagonist activity at human TRPV4 assessed as inhibition of 4alpha-PDD-induced activation	ic50	0.0010	uM
2-[(3R,4S)-4-(4-cyano-3-fluorophenoxy)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-5-(trifluoromethyl)benzonitrile	1363314: Antagonist activity at human TRPV4 expressed in BHK/AC9 or HEK MSR2 cells assessed as inhibition of PF-04674114-induced Ca2+ flux pre-incubated for 10 mins before agonist addition by FLIPR assay	ic50	0.0010	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[8-[5-(trifluoromethyl)pyrimidin-2-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]methanone	1481466: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of 4alphaPDD-induced activation pretreated for 5 mins followed by 4alphaPDD stimulation measured for 5 mins by FLIPR assay	ic50	0.0010	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[(3R)-3-methyl-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]methanone	1481466: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of 4alphaPDD-induced activation pretreated for 5 mins followed by 4alphaPDD stimulation measured for 5 mins by FLIPR assay	ic50	0.0010	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[(1R,5S)-3-[(2R)-3,3,3-trifluoro-2-hydroxypropoxy]imino-8-azabicyclo[3.2.1]octan-8-yl]methanone	1316747: Antagonist activity at human TRPV4 assessed as inhibition of 4alpha-PDD-induced activation	ic50	0.0011	uM
N-[4-cyclobutyl-5-(2-piperidin-1-ylethyl)-1,3-thiazol-2-yl]-1-(5-fluoro-2-pyridinyl)-5-methylpyrazole-4-carboxamide;dihydrochloride	1588942: Inhibition of human TRPV4 expressed in HEK293 cells assessed as reduction in Ca2+ influx incubated for 30 mins by Fluo4-AM dye based	ic50	0.0012	uM
3-[[(5S,7S)-3-(5-tert-butylpyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl]methyl]benzimidazole-5-carbonitrile	1511301: Inhibition of human TRPV4 expressed in baculovirus infected HEK/MSR 2 cells pre-incubated for 10 mins followed by GSK634775A addition by Fura-2 dye based FLIPR assay	ic50	0.0012	uM
3-[[(5S,7S)-3-(2-methoxyphenyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl]methyl]benzimidazole-5-carbonitrile	1511301: Inhibition of human TRPV4 expressed in baculovirus infected HEK/MSR 2 cells pre-incubated for 10 mins followed by GSK634775A addition by Fura-2 dye based FLIPR assay	ic50	0.0012	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[3-[6-(trifluoromethyl)pyridazin-3-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone	1481467: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of hypotonicity-induced activation pretreated for 5 mins followed by hypotonic solution addition measured for 5 mins by FLIPR assay	ic50	0.0013	uM
[6-[[4-(2,5-dimethylpyrazol-3-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[3-[5-(trifluoromethyl)pyrimidin-2-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone	1481466: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of 4alphaPDD-induced activation pretreated for 5 mins followed by 4alphaPDD stimulation measured for 5 mins by FLIPR assay	ic50	0.0013	uM
N-[(3S)-3-amino-4-(4-cyano-3-fluorophenoxy)butyl]-4-cyano-2-(trifluoromethyl)benzenesulfonamide	1700939: Antagonist activity at human TRPV4 expressed in BHK or HEK MSR2 cells assessed as inhibition of TRPV4 agonist GSK634775 (EC80)-induced response incubated for 10 mins	ic50	0.0013	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[3-[5-(trifluoromethyl)-2-pyridinyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone	1481467: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of hypotonicity-induced activation pretreated for 5 mins followed by hypotonic solution addition measured for 5 mins by FLIPR assay	ic50	0.0014	uM
3-[[(5S,7S)-3-(5-cyclopropylpyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl]methyl]benzimidazole-5-carbonitrile	1511301: Inhibition of human TRPV4 expressed in baculovirus infected HEK/MSR 2 cells pre-incubated for 10 mins followed by GSK634775A addition by Fura-2 dye based FLIPR assay	ic50	0.0015	uM
3-[[(5S,7S)-3-(3-ethoxyphenyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl]methyl]benzimidazole-5-carbonitrile	1511301: Inhibition of human TRPV4 expressed in baculovirus infected HEK/MSR 2 cells pre-incubated for 10 mins followed by GSK634775A addition by Fura-2 dye based FLIPR assay	ic50	0.0016	uM
methyl 8-[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]pyridine-3-carbonyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate	1316747: Antagonist activity at human TRPV4 assessed as inhibition of 4alpha-PDD-induced activation	ic50	0.0017	uM
3-[[(5S,7S)-7-methyl-3-(2-methylphenyl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl]methyl]benzimidazole-5-carbonitrile	1511301: Inhibition of human TRPV4 expressed in baculovirus infected HEK/MSR 2 cells pre-incubated for 10 mins followed by GSK634775A addition by Fura-2 dye based FLIPR assay	ic50	0.0017	uM
methyl 9-[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]pyridine-3-carbonyl]-3,9-diazabicyclo[3.3.1]nonane-3-carboxylate	1316747: Antagonist activity at human TRPV4 assessed as inhibition of 4alpha-PDD-induced activation	ic50	0.0018	uM
[6-[[4-[2-(1-hydroxyethyl)-4-methyl-1,3-thiazol-5-yl]-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[3-[5-(trifluoromethyl)pyrimidin-2-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone	1481466: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of 4alphaPDD-induced activation pretreated for 5 mins followed by 4alphaPDD stimulation measured for 5 mins by FLIPR assay	ic50	0.0018	uM
3-[[(5S,7S)-3-[5-(2-hydroxypropan-2-yl)pyrazin-2-yl]-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl]methyl]benzimidazole-5-carbonitrile	1511301: Inhibition of human TRPV4 expressed in baculovirus infected HEK/MSR 2 cells pre-incubated for 10 mins followed by GSK634775A addition by Fura-2 dye based FLIPR assay	ic50	0.0018	uM
[(1R,5S)-8-[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]pyridine-3-carbonyl]-8-azabicyclo[3.2.1]octan-3-yl] N-ethylcarbamate	1316747: Antagonist activity at human TRPV4 assessed as inhibition of 4alpha-PDD-induced activation	ic50	0.0019	uM
N-[4-cyclobutyl-5-(4-methylpiperazin-1-yl)-1,3-thiazol-2-yl]-1-(4-fluorophenyl)-5-methylpyrazole-4-carboxamide	1588942: Inhibition of human TRPV4 expressed in HEK293 cells assessed as reduction in Ca2+ influx incubated for 30 mins by Fluo4-AM dye based	ic50	0.0019	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[(3S)-3-methyl-4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl]methanone	1481466: Antagonist activity at recombinant human TRPV4 expressed in CHOK1 cells assessed as inhibition of 4alphaPDD-induced activation pretreated for 5 mins followed by 4alphaPDD stimulation measured for 5 mins by FLIPR assay	ic50	0.0020	uM
5-chloro-2-[(3R,4S)-4-(4-cyanophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile	1586307: Antagonist activity at human TRPV4 expressed in BHK/AC9 cells assessed as inhibition of GSK634775-induced calcium immobilization pre-incubated for 10 mins followed by agonist addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0020	uM
4-[(3S,4R)-1-(2,4-dichlorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonyl-2-fluorobenzonitrile	1586307: Antagonist activity at human TRPV4 expressed in BHK/AC9 cells assessed as inhibition of GSK634775-induced calcium immobilization pre-incubated for 10 mins followed by agonist addition by Fluo-4-AM dye-based FLIPR assay	ic50	0.0020	uM
[6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]-3-pyridinyl]-[3-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone	1316747: Antagonist activity at human TRPV4 assessed as inhibition of 4alpha-PDD-induced activation	ic50	0.0021	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide	affects binding, increases activity, increases response to substance	5
phorbol-12,13-didecanoate	increases import, increases reaction, affects binding, increases activity	4
Tetrachlorodibenzodioxin	affects expression, increases expression	3
sodium arsenite	decreases expression, increases expression, increases methylation	2
bisphenol A	affects cotreatment, increases methylation	1
tanshinone	increases expression, increases degradation, decreases reaction, increases activity	1
bisphenol S	affects cotreatment, increases expression	1
HC-067047	increases activity, increases expression, decreases reaction	1
Fulvestrant	affects cotreatment, increases methylation	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Vehicle Emissions	decreases reaction, increases expression, increases reaction, increases secretion, affects binding	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Calcium	increases reaction, increases import	1
Cannabidiol	affects activity	1
Cycloheximide	increases degradation, decreases reaction	1
Dexamethasone	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Methylcholanthrene	affects binding, increases reaction	1
Silicon Dioxide	decreases expression	1
Sodium	affects abundance	1
Tretinoin	increases expression	1
1-Methyl-3-isobutylxanthine	increases expression, affects cotreatment	1
Eicosanoids	affects activity	1
Cyclosporine	decreases expression	1
Arachidonic Acid	increases activity	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

99 unique, capped per target: 94 binding, 5 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1118230	Functional	Antagonist activity at human TRPV4 channel	Transient receptor potential ankyrin 1 (TRPA1) channel as emerging target for novel analgesics and anti-inflammatory agents. — J Med Chem
CHEMBL1252948	Binding	Activation of TRPV4 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

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_A9Z3	MCRIi001-A-3	Induced pluripotent stem cell	Male
CVCL_A9Z4	MCRIi001-A-4	Induced pluripotent stem cell	Male
CVCL_D1JD	PrecisION hTRPV4-HEK	Transformed cell line	Female
CVCL_D6A7	HyCyte HEK293T KO-hTRPV4	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00331656	PHASE4	UNKNOWN	Comparative Study of Non-Invasive Mask Ventilation vs Cuirass Ventilation in Patients With Acute Respiratory Failure.
NCT00994552	PHASE4	UNKNOWN	Comparison of Pressure Support and Pressure Control Ventilation in Chronic Respiratory Failure
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00942227	PHASE3	COMPLETED	The Value of Traction in Treatment of Lumbar Radiculopathy
NCT00979108	PHASE3	COMPLETED	The Value of Traction in the Treatment of Cervical Radiculopathy
NCT01826487	PHASE3	COMPLETED	Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
NCT02090959	PHASE3	TERMINATED	An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
NCT02436096	PHASE3	COMPLETED	A Study to Evaluate eFFIcacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With fibRoMyalgia
NCT02829814	PHASE3	TERMINATED	Repeat of: A Study to Evaluate Efficacy and Safety of Sublingual TNX-102 SL Tablet Taken at Bedtime in Patients With Fibromyalgia
NCT03179631	PHASE3	COMPLETED	Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy
NCT05126758	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Deramiocel (CAP-1002) in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT05156320	PHASE3	COMPLETED	Efficacy and Safety of Apitegromab in Patients With Later-Onset Spinal Muscular Atrophy Treated With Nusinersen or Risdiplam
NCT05337553	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Participants With Spinal Muscular Atrophy
NCT05626855	PHASE3	ACTIVE_NOT_RECRUITING	Long-Term Safety & Efficacy of Apitegromab in Patients With SMA Who Completed Previous Trials of Apitegromab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT01074359	PHASE2	TERMINATED	Safety and Efficacy Study of A0001 in Patients With the A3243G Mitochondrial DNA Point Mutation
NCT01371149	PHASE2	COMPLETED	Patient -Ventilator Interaction in Chronic Respiratory Failure
NCT02022072	PHASE2	TERMINATED	Evaluation of Vital Capacity
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03406780	PHASE2	COMPLETED	A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT03921528	PHASE2	COMPLETED	An Active Treatment Study of SRK-015 in Patients With Type 2 or Type 3 Spinal Muscular Atrophy
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT06339580	PHASE2	RECRUITING	Assessment of Volume-targeted Ventilation in Patients With Neuromuscular Disease
NCT07071935	PHASE2	NOT_YET_RECRUITING	A Clinical Trial of Early Ventilation in Amyotrophic Lateral Sclerosis (EVENT ALS)
NCT07287189	PHASE2	RECRUITING	Phase 2 Study of SAT-3247 in Pediatric Ambulatory Patients
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT00252252	PHASE1	COMPLETED	AutoVPAP Versus VPAP; Assessment of Sleep and Ventilation
NCT01560741	PHASE1	UNKNOWN	Telemedicine and Ventilator Titration in Chronic Respiratory Patients Initiating Non-invasive Ventilation
NCT01621984	PHASE1	COMPLETED	Therapeutic Riding and Neuromuscular Disease
NCT01758510	PHASE1	COMPLETED	Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis
NCT03440034	PHASE1	COMPLETED	Study of Pioglitazone in Sporadic Inclusion Body Myositis