TRPM4

Summary

TRPM4 (transient receptor potential cation channel subfamily M member 4, HGNC:17993) is a protein-coding gene on chromosome 19q13.33, encoding Transient receptor potential cation channel subfamily M member 4 (Q8TD43). Calcium-activated selective cation channel that mediates membrane depolarization.

The protein encoded by this gene is a calcium-activated nonselective ion channel that mediates transport of monovalent cations across membranes, thereby depolarizing the membrane. The activity of the encoded protein increases with increasing intracellular calcium concentration, but this channel does not transport calcium.

Source: NCBI Gene 54795 — RefSeq curated summary.

At a glance

• Gene–disease (curated): progressive familial heart block type IB (Strong, GenCC) — +4 more curated relationships
• Clinical variants (ClinVar): 2,259 total — 2 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 35
• Druggable target: yes
• MANE Select transcript: NM_017636

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17993
Approved symbol	TRPM4
Name	transient receptor potential cation channel subfamily M member 4
Location	19q13.33
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20041
Ensembl gene	ENSG00000130529
Ensembl biotype	protein_coding
OMIM	606936
Entrez	54795

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 11 protein_coding, 5 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000252826, ENST00000427978, ENST00000594568, ENST00000595071, ENST00000595519, ENST00000595882, ENST00000596338, ENST00000597316, ENST00000598502, ENST00000598691, ENST00000598697, ENST00000599459, ENST00000599628, ENST00000601347, ENST00000864589, ENST00000864590, ENST00000864591, ENST00000864592, ENST00000864593, ENST00000963018

RefSeq mRNA: 6 — MANE Select: NM_017636 NM_001195227, NM_001321281, NM_001321282, NM_001321283, NM_001321285, NM_017636

CCDS: CCDS33073, CCDS56098

Canonical transcript exons

ENST00000252826 — 25 exons

Exon	Start	End
ENSE00003480398	49188946	49189091
ENSE00003482625	49190208	49190320
ENSE00003506882	49183078	49183212
ENSE00003507894	49211164	49211269
ENSE00003508598	49201964	49202141
ENSE00003511795	49196440	49196874
ENSE00003515690	49211494	49211836
ENSE00003521729	49211015	49211087
ENSE00003537815	49182578	49182922
ENSE00003539933	49158192	49158259
ENSE00003550622	49210710	49210842
ENSE00003559266	49168553	49168736
ENSE00003563097	49190696	49190773
ENSE00003568557	49168260	49168423
ENSE00003585464	49171357	49171418
ENSE00003597142	49200300	49200432
ENSE00003601525	49200611	49200785
ENSE00003618659	49171578	49171769
ENSE00003626424	49172009	49172108
ENSE00003644714	49181349	49181461
ENSE00003647162	49167917	49168097
ENSE00003653988	49188641	49188770
ENSE00003687445	49166041	49166215
ENSE00003694566	49210209	49210405
ENSE00003737753	49157792	49157890

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 99.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.6817 / max 396.1669, expressed in 1630 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
176947	4.9182	1482
176946	2.3875	1276
176948	1.4900	607
176953	1.1160	209
176952	0.6340	244
176954	0.0580	11
176951	0.0511	16
176955	0.0269	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	99.00	gold quality
rectum	UBERON:0001052	98.73	gold quality
apex of heart	UBERON:0002098	97.98	gold quality
metanephros cortex	UBERON:0010533	97.84	gold quality
transverse colon	UBERON:0001157	97.59	gold quality
minor salivary gland	UBERON:0001830	97.37	gold quality
right uterine tube	UBERON:0001302	96.93	gold quality
skin of leg	UBERON:0001511	96.87	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.73	gold quality
skin of abdomen	UBERON:0001416	96.58	gold quality
descending thoracic aorta	UBERON:0002345	96.07	gold quality
gall bladder	UBERON:0002110	96.02	gold quality
left lobe of thyroid gland	UBERON:0001120	95.90	gold quality
right lobe of thyroid gland	UBERON:0001119	95.87	gold quality
body of stomach	UBERON:0001161	95.86	gold quality
ascending aorta	UBERON:0001496	95.86	gold quality
thoracic aorta	UBERON:0001515	95.79	gold quality
right coronary artery	UBERON:0001625	95.48	gold quality
right atrium auricular region	UBERON:0006631	95.48	gold quality
colonic epithelium	UBERON:0000397	95.46	gold quality
aorta	UBERON:0000947	95.08	gold quality
left coronary artery	UBERON:0001626	94.86	gold quality
popliteal artery	UBERON:0002250	94.84	gold quality
tibial artery	UBERON:0007610	94.82	gold quality
small intestine	UBERON:0002108	94.73	gold quality
thyroid gland	UBERON:0002046	94.36	gold quality
upper lobe of left lung	UBERON:0008952	94.25	gold quality
mucosa of stomach	UBERON:0001199	94.06	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.88	gold quality
lower esophagus	UBERON:0013473	93.87	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6379	no	6.46
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting TRPM4, 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-4283	100.00	66.42	2097
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-6780A-3P	98.42	67.49	1518
HSA-MIR-4717-5P	98.19	67.97	894
HSA-MIR-5087	98.01	69.09	965
HSA-MIR-4485-3P	93.21	62.11	61

Literature-anchored findings (GeneRIF, showing 40)

• Voltage dependence is not due to block by divalent cations or to voltage-dependent binding of intracellular Ca2+ to an activator site, indicating that TRPM4 is a transient receptor potential channel with an intrinsic voltage-sensing mechanism. (PMID:12799367)
• TRPM4-mediated depolarization modulates Ca2+ oscillations, with downstream effects on cytokine production in T lymphocytes (PMID:15550671)
• the Ca(2+) sensitivity of TRPM4 is regulated by ATP, PKC-dependent phosphorylation, and calmodulin binding at the C terminus. (PMID:15590641)
• analysis of selectivity filter of the cation channel TRPM4 (PMID:15845551)
• hydrolysis of PI(4,5)P(2) underlies desensitization of TRPM4, and PI(4,5)P(2) is a general regulator for the gating of TRPM ion channels (PMID:16186107)
• PIP2 is a strong positive modulator of TRPM4 and implicate the C-terminal PH domain in PIP2 action. (PMID:16424899)
• evidence indicates a role as a regulator of membrane potential, and thus the driving force for Ca2+ entry from the extracellular medium–{REVIEW} (PMID:17217063)
• This study is believed to provide the first clear evidence that TRPM4b interacts physically with TRPC3. (PMID:18262493)
• Depolarizing currents generated by TRPM4 are an important component in the control of intracellular Ca(2+) signals necessary for insulin secretion and perhaps glucagon from alpha-cells. (PMID:19063936)
• In 3 branches of a large South African Afrikaner pedigree with an autosomal-dominant form of progressive familial heart block type I, identified the mutation c.19G–>A, which attenuated deSUMOylation of the TRPM4 channel. (PMID:19726882)
• TRPM4 gene is a causative gene in isolated cardiac conduction disease with mutations resulting in a gain of function and TRPM4 channel being highly expressed in cardiac Purkinje fibers. (PMID:20562447)
• These results identify TRPM4 as an important, unanticipated regulator of the beta-catenin pathway, where aberrant signaling is frequently associated with cancer. (PMID:20625999)
• Cys(1093) residue of TRPM4 is crucial for the H(2)O(2)-mediated loss of desensitization. (PMID:20884614)
• In eight probands with atrioventricular block or right bundle branch block-five familial cases and three sporadic cases-a total of six novel and two published TRPM4 mutations were identified. (PMID:21887725)
• TRPM4 possesses the biophysical properties and upstream cellular signaling and regulatory pathways that establish it as a major physiological player in smooth muscle membrane depolarization. (PMID:23116477)
• TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis. (PMID:23160238)
• Because of its effect on the resting membrane potential, reduction or increase of TRPM4 channel function may both reduce the availability of sodium channel and thus lead to Brugada syndrome . (PMID:23382873)
• No role was found for TRPM4 in the peripheral blood compartment of multiple sclerosis patients. (PMID:23796873)
• Used the Xenopus laevis oocyte expression system for expression, purification and extraction of functional human TRPM4 protein. Investigated the supra-molecular assembly of TRPM4. (PMID:24333049)
• TRPM4 protein is a ROS-modulated non-selective cationic channel that performs several cell functions, including regulating intracellular Ca(2+) overload and Ca(2+) oscillation (PMID:24518820)
• Contraction of cerebral artery smooth muscle cells requires the integration of pressure-sensing signaling pathways and depolarization through the activation of TRPM4. (PMID:24866019)
• TRPM4 is an important regulator of Ca2+ signals generated by histamine in hASCs and is required for adipogenesis. (PMID:25001294)
• These results showed that the cell surface expression of TRPM4 channels is mediated by 14-3-3gamma binding. (PMID:25047048)
• Casein kinase 1 phosphorylates S839 and is responsible for the basolateral localization of TRPM4. (PMID:25231975)
• TRPM4 acts to maintain endothelial features and its loss promotes fibrotic conversion via TGF-beta production. (PMID:25909699)
• new insight into the ligand binding domains of the TRPM4 channel (PMID:26071843)
• we demonstrate that the inhibition of TRPM4 activity alters cellular contractility in vivo, affecting cutaneous wound healing. (PMID:26110647)
• these data suggest an important role for the Sur1-Trpm4 channel in the pathophysiology of postischemic cell death (PMID:26172285)
• Identify TRPM4 as a regulator of store operated calcium entry in prostate tumor cells, and demonstrate a role for TRPM4 in cancer cell migration. (PMID:26496025)
• The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na(+)-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca(2+) from thapsigargin-sensitive Ca(2+) stores (PMID:26571400)
• TRPM4 protein expression is widely expressed in benign and cancerous prostate tissue (PMID:26590985)
• TRPM4 channels regulate human detrusor smooth muscle excitability and contractility and are critical determinants of human urinary bladder function (PMID:26791488)
• A large pedigree diagnosed with progressive familial heart block type I was linked to a mutation of the TRPM4 ion channel. (PMID:26820365)
• The loss-of-function variants A432T/G582S found in 2 unrelated patients with atrioventricular block are most likely caused by misfolding-dependent altered trafficking. (PMID:27207958)
• TRPM4 protein expression is up-regulated in diffuse large B cell lymphoma (PMID:28248435)
• Study supports the view that TRPM4 variants could be responsible for about 2% of LQT syndrome cases. The impact of these variants results in electrophysical disturbances. (PMID:28315637)
• We identified a double heterozygosity for pathogenic mutations in SCN5A and TRPM4 in a Brugada syndrome patient. (PMID:28494446)
• This study presents further evidence to show that TRPM4 regulates beta-catenin signaling and enhances the proliferation of prostate cancer cell lines, through a calcium-dependent regulation of Akt1 and GSK-3beta activity. (PMID:28614631)
• electron cryo-microscopy structure of the most widespread CAN channel, human TRPM4, bound to the agonist Ca(2+) and the modulator decavanadate (PMID:29211723)
• study presents 2 structures of TRPM4 embedded in lipid nanodiscs at ~3-angstrom resolution, as determined by single-particle cryo-electron microscopy; these structures, with and without calcium bound, reveal a general architecture for this major subfamily of TRP channels and a well-defined calcium-binding site within the intracellular side of the S1-S4 domain (PMID:29217581)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
danio_rerio	trpm4a	ENSDARG00000059993
danio_rerio	trpm4b3	ENSDARG00000063347
danio_rerio	trpm4b.2	ENSDARG00000063435
danio_rerio	trpm4b.1	ENSDARG00000109442
mus_musculus	Trpm4	ENSMUSG00000038260
rattus_norvegicus	Trpm4	ENSRNOG00000020714
drosophila_melanogaster	Trpm	FBGN0265194
caenorhabditis_elegans		WBGENE00000425
caenorhabditis_elegans	gon-2	WBGENE00001651
caenorhabditis_elegans		WBGENE00004149
caenorhabditis_elegans		WBGENE00020972
caenorhabditis_elegans		WBGENE00021404
caenorhabditis_elegans		WBGENE00021408

Paralogs (7): TRPM5 (ENSG00000070985), TRPM3 (ENSG00000083067), TRPM7 (ENSG00000092439), TRPM6 (ENSG00000119121), TRPM1 (ENSG00000134160), TRPM2 (ENSG00000142185), TRPM8 (ENSG00000144481)

Protein

Protein identifiers

Transient receptor potential cation channel subfamily M member 4 — Q8TD43 (reviewed: Q8TD43)

Alternative names: Calcium-activated non-selective cation channel 1, Long transient receptor potential channel 4, Melastatin-4

All UniProt accessions (7): Q8TD43, A0A087X0Z3, M0QX92, M0QYK7, M0QZ19, M0R0H1, M0R3H6

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-activated selective cation channel that mediates membrane depolarization. While it is activated by increase in intracellular Ca(2+), it is impermeable to it. Mediates transport of monovalent cations (Na(+) > K(+) > Cs(+) > Li(+)), leading to depolarize the membrane. It thereby plays a central role in cadiomyocytes, neurons from entorhinal cortex, dorsal root and vomeronasal neurons, endocrine pancreas cells, kidney epithelial cells, cochlea hair cells etc. Participates in T-cell activation by modulating Ca(2+) oscillations after T lymphocyte activation, which is required for NFAT-dependent IL2 production. Involved in myogenic constriction of cerebral arteries. Controls insulin secretion in pancreatic beta-cells. May also be involved in pacemaking or could cause irregular electrical activity under conditions of Ca(2+) overload. Affects T-helper 1 (Th1) and T-helper 2 (Th2) cell motility and cytokine production through differential regulation of calcium signaling and NFATC1 localization. Enhances cell proliferation through up-regulation of the beta-catenin signaling pathway. Plays a role in keratinocyte differentiation. Lacks channel activity.

Subunit / interactions. Homotetramer.

Subcellular location. Cell membrane. Endoplasmic reticulum. Golgi apparatus Cell membrane. Golgi apparatus.

Tissue specificity. Widely expressed with a high expression in intestine and prostate. In brain, it is both expressed in whole cerebral arteries and isolated vascular smooth muscle cells. Prominently expressed in Purkinje fibers. Expressed at higher levels in T-helper 2 (Th2) cells as compared to T-helper 1 (Th1) cells. Expressed in keratocytes.

Post-translational modifications. Phosphorylation by PKC leads to increase the sensitivity to Ca(2+). Sumoylated. Desumoylated by SENP1.

Disease relevance. Progressive familial heart block 1B (PFHB1B) [MIM:604559] A cardiac bundle branch disorder characterized by progressive alteration of cardiac conduction through the His-Purkinje system, with a pattern of a right bundle-branch block and/or left anterior hemiblock occurring individually or together. It leads to complete atrio-ventricular block causing syncope and sudden death. The disease is caused by variants affecting the gene represented in this entry. Erythrokeratodermia variabilis et progressiva 6 (EKVP6) [MIM:618531] A form of erythrokeratodermia variabilis et progressiva, a genodermatosis characterized by the coexistence of two independent skin lesions: transient erythema and hyperkeratosis that is usually localized but occasionally occurs in its generalized form. Clinical presentation varies significantly within a family and from one family to another. Palmoplantar keratoderma is present in around 50% of cases. EKVP6 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Displays weak voltage dependence, and repressed by decavanadate. Calmodulin-binding confers the Ca(2+) sensitivity. ATP is able to restore Ca(2+) sensitivity after desensitization. ATP inhibits channel activity. Phosphatidylinositol 4,5-bisphosphate (PIP2)-binding strongly enhances activity, by increasing the channel’s Ca(2+) sensitivity and shifting its voltage dependence of activation towards negative potentials. Activity is also enhanced by 3,5-bis(trifluoromethyl)pyrazole derivative (BTP2). Exhibits pronounced temperature sensitivity, with activities strongly intensifying near physiological temperatures.

Domain organisation. TRPM4, is a temperature-sensitive ion channel, it adopts distinct conformations at different temperatures, markedly influencing where and how ligands interact with it. Decavanadate (a positive modulator), ATP (an inhibitor) and Ca(2+) bind to different locations of TRPM4 at physiological temperatures or at lower temperatures.

Similarity. Belongs to the transient receptor (TC 1.A.4) family. LTrpC subfamily. TRPM4 sub-subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8TD43-1	1, TRPM4b	yes
Q8TD43-2	2, TRPM4a
Q8TD43-3	3, TRPM4c

RefSeq proteins (6): NP_001182156, NP_001308210, NP_001308211, NP_001308212, NP_001308214, NP_060106* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005821	Ion_trans_dom	Domain
IPR041491	TRPM_SLOG	Domain
IPR050927	TRPM	Family
IPR057366	TRPM-like	Domain

Pfam: PF00520, PF18139, PF25508

Catalyzed reactions (Rhea), 2 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (178 total): helix 50, strand 32, mutagenesis site 22, sequence variant 19, binding site 13, turn 12, topological domain 8, transmembrane region 6, sequence conflict 4, region of interest 2, modified residue 2, splice variant 2, chain 1, intramembrane region 1, coiled-coil region 1, short sequence motif 1, glycosylation site 1, disulfide bond 1

Structure

Experimental structures (PDB)

29 structures.

PDB	Method	Resolution (Å)
9MRT	ELECTRON MICROSCOPY	2.44
9MTC	ELECTRON MICROSCOPY	2.63
9MTA	ELECTRON MICROSCOPY	2.78
30LA	ELECTRON MICROSCOPY	3
30LD	ELECTRON MICROSCOPY	3
9B8X	ELECTRON MICROSCOPY	3
30KW	ELECTRON MICROSCOPY	3.1
6BQV	ELECTRON MICROSCOPY	3.1
9B8W	ELECTRON MICROSCOPY	3.1
9B93	ELECTRON MICROSCOPY	3.1
9B94	ELECTRON MICROSCOPY	3.1
9MT8	ELECTRON MICROSCOPY	3.19
6BQR	ELECTRON MICROSCOPY	3.2
9B8Y	ELECTRON MICROSCOPY	3.2
9Y2B	ELECTRON MICROSCOPY	3.2
9B91	ELECTRON MICROSCOPY	3.3
9Y2A	ELECTRON MICROSCOPY	3.3
30KZ	ELECTRON MICROSCOPY	3.4
9B8Z	ELECTRON MICROSCOPY	3.4
9B90	ELECTRON MICROSCOPY	3.4
9Y2C	ELECTRON MICROSCOPY	3.4
9I3R	ELECTRON MICROSCOPY	3.46
8RCU	ELECTRON MICROSCOPY	3.5
9B92	ELECTRON MICROSCOPY	3.5
8RCR	ELECTRON MICROSCOPY	3.6
6BWI	ELECTRON MICROSCOPY	3.7
5WP6	ELECTRON MICROSCOPY	3.8
9SMK	ELECTRON MICROSCOPY	3.8
8RD9	ELECTRON MICROSCOPY	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TD43-F1	78.51	0.27

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 (13): 171; 214; 225; 270; 392; 395; 396; 421 (in other chain); 448 (in other chain); 828; 831; 865 …

Post-translational modifications (2): 1145, 1152

Disulfide bonds (1): 993–1011

Glycosylation sites (1): 992

Mutagenesis-validated functional residues (22):

Position	Phenotype
275	abolishes ability to restore sensitivity to ca(2+) after desensitization.
278	no effect.
279	no effect.
324	no effect.
325	abolishes ability to restore sensitivity to ca(2+) after desensitization.
327	no effect.
396	loss of the temperature-induced potentiation. inability to activate at negative membrane potentials.
597	becomes insensitive to decavanadate’s voltage modulation effect.
613	becomes insensitive to decavanadate’s voltage modulation effect.
664	becomes insensitive to decavanadate’s voltage modulation effect.
925	becomes insensitive to decavanadate’s voltage modulation effect.
977	alters the monovalent cation permeability sequence and results in a pore with moderate ca(2+) permeability.
981–986	induces a functional channel that combines the gating hallmarks of trpm4 (activation by ca(2+)) with trpv6-like sensitiv
981	results in a channel with normal permeability properties but with a reduced sensitivity to block by intracellular spermi
982	results in a functional channel that exhibits extremely fast desensitization, possibly indicating destabilization of the
984	results in a non-functional channel with a dominant negative phenotype.
1049	becomes insensitive to decavanadate’s voltage modulation effect.
1059	does not affect pip2-binding.
1072	does not affect pip2-binding.
1136–1141	results in a channel with very rapid desensitization and highly reduced sensitivity to pip2.
1145	decreases the sensitivity to ca(2+).
1152	decreases the sensitivity to ca(2+).

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3295583	TRP channels
R-HSA-9717207	Sensory perception of sweet, bitter, and umami (glutamate) taste

MSigDB gene sets: 390 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_BUNDLE_OF_HIS_CELL_TO_PURKINJE_MYOCYTE_COMMUNICATION, GOBP_DENDRITIC_CELL_MIGRATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_MEMBRANE_DEPOLARIZATION_DURING_ACTION_POTENTIAL, GOBP_POSITIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_INSULIN_SECRETION, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS

GO Biological Process (34): adaptive immune response (GO:0002250), dendritic cell chemotaxis (GO:0002407), regulation of T cell cytokine production (GO:0002724), positive regulation of cytosolic calcium ion concentration (GO:0007204), positive regulation of cell population proliferation (GO:0008284), positive regulation of heart rate (GO:0010460), protein sumoylation (GO:0016925), calcium-mediated signaling (GO:0019722), metal ion transport (GO:0030001), negative regulation of bone mineralization (GO:0030502), positive regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0035774), positive regulation of fat cell differentiation (GO:0045600), negative regulation of osteoblast differentiation (GO:0045668), positive regulation of vasoconstriction (GO:0045907), protein homotetramerization (GO:0051289), calcium ion transmembrane transport (GO:0070588), cellular response to ATP (GO:0071318), membrane depolarization during AV node cell action potential (GO:0086045), membrane depolarization during Purkinje myocyte cell action potential (GO:0086047), membrane depolarization during bundle of His cell action potential (GO:0086048), regulation of heart rate by cardiac conduction (GO:0086091), positive regulation of canonical Wnt signaling pathway (GO:0090263), monoatomic cation transmembrane transport (GO:0098655), obsolete inorganic cation transmembrane transport (GO:0098662), sodium ion import across plasma membrane (GO:0098719), regulation of ventricular cardiac muscle cell action potential (GO:0098911), positive regulation of atrial cardiac muscle cell action potential (GO:1903949), positive regulation of adipose tissue development (GO:1904179), positive regulation of regulation of vascular associated smooth muscle cell membrane depolarization (GO:1904199), immune system process (GO:0002376), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (12): calcium-activated cation channel activity (GO:0005227), calcium channel activity (GO:0005262), sodium channel activity (GO:0005272), calcium ion binding (GO:0005509), calmodulin binding (GO:0005516), ATP binding (GO:0005524), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), monoatomic ion channel activity (GO:0005216), protein binding (GO:0005515), metal ion binding (GO:0046872), metal ion transmembrane transporter activity (GO:0046873)

GO Cellular Component (7): nucleoplasm (GO:0005654), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), membrane (GO:0016020), sodium channel complex (GO:0034706), neuronal cell body (GO:0043025)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Stimuli-sensing channels	1
Sensory perception of taste	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
membrane depolarization during cardiac muscle cell action potential	3
monoatomic cation channel activity	2
protein binding	2
cellular anatomical structure	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
immune response	1
leukocyte chemotaxis	1
dendritic cell migration	1
T cell cytokine production	1
regulation of T cell mediated immunity	1
regulation of cytokine production involved in immune response	1
regulation of biological quality	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regulation of heart rate	1
positive regulation of heart contraction	1
peptidyl-lysine modification	1
protein modification by small protein conjugation	1
intracellular signaling cassette	1
monoatomic cation transport	1
negative regulation of ossification	1
bone mineralization	1
regulation of bone mineralization	1
negative regulation of biomineral tissue development	1
positive regulation of insulin secretion	1
insulin secretion involved in cellular response to glucose stimulus	1
regulation of insulin secretion involved in cellular response to glucose stimulus	1
fat cell differentiation	1
positive regulation of cell differentiation	1
regulation of fat cell differentiation	1
osteoblast differentiation	1
negative regulation of cell differentiation	1
regulation of osteoblast differentiation	1
regulation of vasoconstriction	1
vasoconstriction	1
positive regulation of multicellular organismal process	1
protein homooligomerization	1

Protein interactions and networks

STRING

1068 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRPM4	ABCC8	Q09428	992
TRPM4	TRPC3	Q13507	942
TRPM4	TRPC6	Q9Y210	867
TRPM4	TRPC1	P48995	848
TRPM4	TRPV2	Q9Y5S1	846
TRPM4	TRPV4	Q9HBA0	844
TRPM4	SCN5A	Q14524	826
TRPM4	KCNA7	Q96RP8	825
TRPM4	TRPA1	O75762	767
TRPM4	MCOLN1	Q9GZU1	756
TRPM4	TRPV1	Q8NER1	743
TRPM4	TRPV3	Q8NET8	743
TRPM4	TRPV6	Q9H1D0	743
TRPM4	TRPV5	Q9NQA5	722
TRPM4	CALM1	P02593	697

IntAct

69 interactions, top by confidence:

A	B	Type	Score
ODAD1	HGS	psi-mi:“MI:0914”(association)	0.850
IFT57	IFT56	psi-mi:“MI:0914”(association)	0.640
ASPH	STXBP3	psi-mi:“MI:0914”(association)	0.640
NIPAL1	ESYT2	psi-mi:“MI:0914”(association)	0.640
TRPM4	S100A5	psi-mi:“MI:0407”(direct interaction)	0.610
S100A5	TRPM4	psi-mi:“MI:0915”(physical association)	0.610
TRPM4	S100A2	psi-mi:“MI:0407”(direct interaction)	0.540
S100A2	TRPM4	psi-mi:“MI:0915”(physical association)	0.540
TRPM4	S100A3	psi-mi:“MI:0407”(direct interaction)	0.540
S100A3	TRPM4	psi-mi:“MI:0915”(physical association)	0.540
TRPM4	S100A4	psi-mi:“MI:0407”(direct interaction)	0.540
S100A4	TRPM4	psi-mi:“MI:0915”(physical association)	0.540
TRPM4	S100A6	psi-mi:“MI:0407”(direct interaction)	0.540
S100A6	TRPM4	psi-mi:“MI:0915”(physical association)	0.540
TRPM4	S100A8	psi-mi:“MI:0407”(direct interaction)	0.540
S100A8	TRPM4	psi-mi:“MI:0915”(physical association)	0.540
TRPM4	S100A10	psi-mi:“MI:0407”(direct interaction)	0.540
S100A10	TRPM4	psi-mi:“MI:0915”(physical association)	0.540
TRPM4	S100A11	psi-mi:“MI:0407”(direct interaction)	0.540
S100A11	TRPM4	psi-mi:“MI:0915”(physical association)	0.540
CCDC107	PLD2	psi-mi:“MI:0914”(association)	0.530
PKD2L2	PKD2	psi-mi:“MI:0914”(association)	0.530
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.530
B4GAT1	ADCY6	psi-mi:“MI:0914”(association)	0.530
CREB3	MYO9A	psi-mi:“MI:0914”(association)	0.530
TRPM4	S100A1	psi-mi:“MI:0407”(direct interaction)	0.440
TRPM4	S100A9	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (80): TRPM4 (Affinity Capture-MS), TRPM4 (Affinity Capture-MS), TRPM4 (Affinity Capture-MS), TRPM4 (Affinity Capture-MS), TRPM4 (Affinity Capture-MS), TRPM4 (Affinity Capture-MS), TRPM4 (Affinity Capture-MS), TRPM4 (Affinity Capture-MS), TRPM4 (Affinity Capture-MS), TRPM4 (Affinity Capture-MS), TRPM4 (Affinity Capture-MS), TRPM4 (Affinity Capture-RNA), TRPM4 (Affinity Capture-MS), TRPM4 (Proximity Label-MS), TRPM4 (Proximity Label-MS)

ESM2 similar proteins: A2BDX4, A4K2T1, A4K2Y2, D4AD53, O15554, O73606, O88454, O89109, P15388, P17971, P17972, P35739, P48547, P59053, P59994, P59995, P97557, Q03719, Q0P583, Q17ST2, Q52PG9, Q5RC10, Q60565, Q63881, Q6IVV8, Q6PIU1, Q7TN37, Q80XM3, Q8BZN2, Q8CFS6, Q8HYZ1, Q8IV77, Q8R1P5, Q8R523, Q8TAE7, Q8TD43, Q8TDN1, Q8TDN2, Q96RP8, Q9ERS0

Diamond homologs: A0A0R4IMY7, A7T1N0, A8DYE2, E9PTA2, J9SQF3, O94759, Q2TV84, Q2WEA5, Q5XIG0, Q7TN37, Q7Z2W7, Q7Z4N2, Q8BVU5, Q8R455, Q8R4D5, Q8TD43, Q91YD4, Q9BW91, Q9ESQ5, Q9HCF6, Q9JJH7, Q9NZQ8, S5UH55, Q09297, Q8CIR4, Q923J1, Q925B3, Q96QT4, Q9BX84, Q93971

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PRKCA	up-regulates	TRPM4	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

2259 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	3
Uncertain significance	1270
Likely benign	728
Benign	82

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
35490	NM_017636.4(TRPM4):c.2741A>G (p.Lys914Arg)	Pathogenic
652588	NM_017636.4(TRPM4):c.3099C>G (p.Ile1033Met)	Pathogenic
3340067	NM_017636.4(TRPM4):c.273C>T (p.Leu91=)	Likely pathogenic
3770	NM_017636.4(TRPM4):c.19G>A (p.Glu7Lys)	Likely pathogenic
444479	NM_017636.4(TRPM4):c.448G>T (p.Gly150Ter)	Likely pathogenic

SpliceAI

3691 predictions. Top by Δscore:

Variant	Effect	Δscore
19:49157887:GCAG:G	donor_gain	1.0000
19:49157889:AGG:A	donor_loss	1.0000
19:49157891:GT:G	donor_loss	1.0000
19:49166211:GCAAT:G	donor_gain	1.0000
19:49168732:GGGAG:G	donor_gain	1.0000
19:49168733:GGAG:G	donor_gain	1.0000
19:49168733:GGAGG:G	donor_gain	1.0000
19:49168734:GAG:G	donor_gain	1.0000
19:49168734:GAGG:G	donor_gain	1.0000
19:49168736:GGT:G	donor_loss	1.0000
19:49168737:G:GG	donor_gain	1.0000
19:49183076:A:AG	acceptor_gain	1.0000
19:49183077:G:GG	acceptor_gain	1.0000
19:49183077:GAT:G	acceptor_gain	1.0000
19:49183209:GATG:G	donor_gain	1.0000
19:49183210:ATGGT:A	donor_loss	1.0000
19:49183211:TGGT:T	donor_loss	1.0000
19:49183212:GGT:G	donor_loss	1.0000
19:49183213:G:T	donor_loss	1.0000
19:49183214:T:A	donor_loss	1.0000
19:49183215:G:GT	donor_loss	1.0000
19:49188719:G:GT	donor_gain	1.0000
19:49188733:G:GT	donor_gain	1.0000
19:49188734:A:T	donor_gain	1.0000
19:49188746:TTC:T	donor_gain	1.0000
19:49190206:A:AG	acceptor_gain	1.0000
19:49190206:AG:A	acceptor_loss	1.0000
19:49190207:G:GA	acceptor_gain	1.0000
19:49190207:GT:G	acceptor_gain	1.0000
19:49190207:GTCT:G	acceptor_gain	1.0000

AlphaMissense

7836 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:49168265:T:A	W152R	0.998
19:49168265:T:C	W152R	0.998
19:49181405:T:A	W403R	0.998
19:49181405:T:C	W403R	0.998
19:49181424:C:A	A409D	0.998
19:49181397:C:A	A400D	0.997
19:49181456:T:A	W420R	0.997
19:49181456:T:C	W420R	0.997
19:49202121:C:A	N1037K	0.997
19:49202121:C:G	N1037K	0.997
19:49181412:G:C	R405P	0.996
19:49200650:T:A	W940R	0.996
19:49200650:T:C	W940R	0.996
19:49181388:T:C	L397P	0.995
19:49181458:G:C	W420C	0.995
19:49181458:G:T	W420C	0.995
19:49210282:T:C	F1069L	0.995
19:49210284:C:A	F1069L	0.995
19:49210284:C:G	F1069L	0.995
19:49168086:C:A	A146D	0.994
19:49172091:T:C	L378S	0.994
19:49181394:T:C	L399S	0.994
19:49183162:T:A	W565R	0.994
19:49183162:T:C	W565R	0.994
19:49200432:G:A	M926I	0.994
19:49200432:G:C	M926I	0.994
19:49200432:G:T	M926I	0.994
19:49202126:T:A	L1039H	0.994
19:49210251:G:C	W1058C	0.994
19:49210251:G:T	W1058C	0.994

dbSNP variants (sampled 300 via entrez): RS1000011672 (19:49188584 C>T), RS1000061839 (19:49191223 T>C), RS1000130417 (19:49166214 A>C,G), RS1000154367 (19:49194301 C>A), RS1000176076 (19:49155832 T>G), RS1000232618 (19:49170716 A>G), RS1000260963 (19:49208845 G>T), RS1000323519 (19:49210489 G>C,T), RS1000418117 (19:49176254 G>A), RS1000420561 (19:49182010 A>G,T), RS1000484983 (19:49204709 T>TA), RS1000494211 (19:49178907 C>T), RS1000553215 (19:49198655 A>G), RS1000561835 (19:49183554 G>A,C), RS1000645679 (19:49158527 C>G,T)

Disease associations

OMIM: gene MIM:606936 | disease phenotypes: MIM:604559, MIM:618531, MIM:609620, MIM:601144, MIM:600996, MIM:604772, MIM:115080, MIM:194200

GenCC curated gene-disease

Disease	Classification	Inheritance
erythrokeratodermia variabilis et progressiva 6	Strong	Autosomal dominant
progressive familial heart block type IB	Strong	Autosomal dominant
erythrokeratodermia variabilis	Supportive	Autosomal dominant
progressive familial heart block	Supportive	Autosomal dominant
Brugada syndrome	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Brugada syndrome	Refuted	AD

Mondo (20): progressive familial heart block type IB (MONDO:0011474), erythrokeratodermia variabilis et progressiva 6 (MONDO:0032801), cardiomyopathy (MONDO:0004994), long QT syndrome (MONDO:0002442), myoepithelial tumor (MONDO:0002380), short QT syndrome (MONDO:0000453), ventricular fibrillation (MONDO:0000190), arrhythmogenic right ventricular cardiomyopathy (MONDO:0016587), Brugada syndrome (MONDO:0015263), cardiac arrest (MONDO:0000745), catecholaminergic polymorphic ventricular tachycardia 1 (MONDO:0011484), conduction system disorder (MONDO:0005449), dilated cardiomyopathy (MONDO:0005021), cardiac conduction defect (MONDO:0100042), restrictive cardiomyopathy (MONDO:0005201)

Orphanet (10): Hereditary progressive cardiac conduction defect (Orphanet:871), Rare cardiomyopathy (Orphanet:167848), Congenital short QT syndrome (Orphanet:51083), Inherited arrhythmogenic cardiomyopathy (Orphanet:247), Brugada syndrome (Orphanet:130), Catecholaminergic polymorphic ventricular tachycardia (Orphanet:3286), Dilated cardiomyopathy (Orphanet:217604), Restrictive cardiomyopathy (Orphanet:217632), Rare hypertrophic cardiomyopathy (Orphanet:217569), NON RARE IN EUROPE: Wolff-Parkinson-White syndrome (Orphanet:907)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000982	Palmoplantar keratoderma
HP:0000989	Pruritus
HP:0001036	Parakeratosis
HP:0001279	Syncope
HP:0001595	Abnormal hair morphology
HP:0001635	Congestive heart failure
HP:0001649	Tachycardia
HP:0001657	Prolonged QT interval
HP:0001662	Bradycardia
HP:0001663	Ventricular fibrillation
HP:0001678	Atrioventricular block
HP:0001695	Cardiac arrest
HP:0002027	Abdominal pain
HP:0002094	Dyspnea
HP:0002321	Vertigo
HP:0003593	Infantile onset
HP:0004308	Ventricular arrhythmia
HP:0004751	Paroxysmal ventricular tachycardia
HP:0004755	Supraventricular tachycardia
HP:0005165	Shortened PR interval
HP:0006482	Abnormal dental morphology
HP:0010783	Erythema
HP:0011675	Arrhythmia
HP:0011704	Sick sinus syndrome
HP:0011705	First degree atrioventricular block
HP:0011710	Bundle branch block
HP:0011711	Left anterior fascicular block
HP:0011712	Complete right bundle branch block
HP:0011715	Trifascicular block

GWAS associations

0 associations (top):

MeSH disease descriptors (17)

Descriptor	Name	Tree numbers
D019571	Arrhythmogenic Right Ventricular Dysplasia	C14.240.400.145; C14.280.238.028; C14.280.400.145; C16.131.240.400.145
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D002313	Cardiomyopathy, Restrictive	C14.280.238.160
D056266	Erythrokeratodermia Variabilis	C16.320.850.337; C17.800.229.606; C17.800.428.304; C17.800.827.337
D006323	Heart Arrest	C14.280.383
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D009208	Myoepithelioma	C04.557.435.585
D017180	Tachycardia, Ventricular	C14.280.067.845.940; C14.280.123.875.940; C23.550.073.845.940
D014693	Ventricular Fibrillation	C14.280.067.922; C23.550.073.922
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
C563409	Arrhythmogenic Right Ventricular Dysplasia, Familial, 2 (supp.)
C536154	Keratoderma palmoplantaris transgrediens (supp.)
C567037	Progressive Familial Heart Block, Type Ib (supp.)
C580439	Short Qt Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1628469 (SINGLE PROTEIN)

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 (17 total), top 17:

Ligand	Action	Affinity	Parameter
BTP2	Agonist	8.1	pEC50
IBA	Channel blocker	6.85	pIC50
NBA	Channel blocker	6.4	pIC50
Ca2+	Agonist	6.3	pEC50
LBA	Channel blocker	5.8	pIC50
ATP	Antagonist	5.8	pIC50
CBA	Antagonist	5.74	pIC50
ADP	Antagonist	5.7	pIC50
decavanadate	Agonist	5.7	pEC50
flufenamic acid	Antagonist	5.6	pIC50
meclofenamic acid	Channel blocker	5.47	pIC50
PIP2	Agonist	5.3	pEC50
9-phenanthrol	Channel blocker	4.78	pIC50
adenosine 5’-monophosphate	Antagonist	4.7	pIC50
AMP-PNP	Antagonist	4.7	pIC50
spermine	Antagonist	4.2	pIC50
adenosine	Channel blocker	3.2	pIC50

ChEMBL bioactivities

15 potent at pChembl≥5 of 21 total, top 15 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.40	IC50	400	nM	CHEMBL1408302
6.23	EC50	588.8	nM	CHEMBL5186500
5.89	IC50	1300	nM	CHEMBL4439848
5.87	EC50	1349	nM	CHEMBL5194924
5.82	IC50	1500	nM	CHEMBL4525597
5.80	IC50	1600	nM	CHEMBL4540384
5.77	EC50	1698	nM	CHEMBL5179994
5.74	EC50	1820	nM	CHEMBL5202815
5.55	IC50	2800	nM	CHEMBL4447880
5.50	EC50	3162	nM	CHEMBL4863993
5.44	IC50	3600	nM	CHEMBL4574460
5.33	IC50	4700	nM	CHEMBL4472038
5.31	IC50	4900	nM	CHEMBL4554529
5.23	IC50	5900	nM	CHEMBL4465106
5.05	EC50	8913	nM	CHEMBL5189636

PubChem BioAssay actives

15 with measured affinity, of 30 total; 15 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
4-chloro-2-[(2-naphthalen-1-yloxyacetyl)amino]benzoic acid	1602016: Inhibition of Flag-tagged TRPM4 (unknown origin) expressed in HEK293 cells assessed as reduction in intracellular Na+ influx after 45 mins by ANG2 dye-based fluorescence assay	ic50	0.4000	uM
[(1S,3S)-7-chloro-1-(3,5-difluorophenyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol	1896974: Agonist activity at human TRPM4 expressed in CHO-K1 cells assessed as increase in relative fluorescence unit by measuring membrane potential by FLIPR assay	ec50	0.5888	uM
2-[[2-(2-chlorophenoxy)acetyl]amino]-6-methylbenzoic acid	1602016: Inhibition of Flag-tagged TRPM4 (unknown origin) expressed in HEK293 cells assessed as reduction in intracellular Na+ influx after 45 mins by ANG2 dye-based fluorescence assay	ic50	1.3000	uM
[(1S,3S)-7-chloro-1-(3-chloro-5-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol	1896974: Agonist activity at human TRPM4 expressed in CHO-K1 cells assessed as increase in relative fluorescence unit by measuring membrane potential by FLIPR assay	ec50	1.3490	uM
4-chloro-2-[[2-(2-chlorophenoxy)acetyl]amino]benzoic acid	1602016: Inhibition of Flag-tagged TRPM4 (unknown origin) expressed in HEK293 cells assessed as reduction in intracellular Na+ influx after 45 mins by ANG2 dye-based fluorescence assay	ic50	1.5000	uM
4-chloro-2-[2-(4-chloro-2-methylphenoxy)propanoylamino]benzoic acid	1602016: Inhibition of Flag-tagged TRPM4 (unknown origin) expressed in HEK293 cells assessed as reduction in intracellular Na+ influx after 45 mins by ANG2 dye-based fluorescence assay	ic50	1.6000	uM
[(1S,3S)-7-chloro-1-(3-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol	1896974: Agonist activity at human TRPM4 expressed in CHO-K1 cells assessed as increase in relative fluorescence unit by measuring membrane potential by FLIPR assay	ec50	1.6982	uM
[(1S,3S)-7-chloro-1-(3-chlorophenyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol	1896974: Agonist activity at human TRPM4 expressed in CHO-K1 cells assessed as increase in relative fluorescence unit by measuring membrane potential by FLIPR assay	ec50	1.8197	uM
4-chloro-2-[[2-(2-chlorophenoxy)acetyl]amino]-N-cyclopropylsulfonylbenzamide	1602016: Inhibition of Flag-tagged TRPM4 (unknown origin) expressed in HEK293 cells assessed as reduction in intracellular Na+ influx after 45 mins by ANG2 dye-based fluorescence assay	ic50	2.8000	uM
5-chloro-N-[(5-chloro-1,3-thiazol-2-yl)methyl]-1,2-benzothiazol-6-amine	1765022: Agonist activity at human TRPM4 expressed in CHO cells assessed as increase in A23187-induced intracellular calcium level by FLIPR assay	ec50	3.1623	uM
2-[[2-(2-chlorophenoxy)acetyl]amino]-4-cyanobenzoic acid	1602016: Inhibition of Flag-tagged TRPM4 (unknown origin) expressed in HEK293 cells assessed as reduction in intracellular Na+ influx after 45 mins by ANG2 dye-based fluorescence assay	ic50	3.6000	uM
2-[[2-(2-chlorophenoxy)acetyl]amino]-4-(1,3-thiazol-2-yl)benzoic acid	1602016: Inhibition of Flag-tagged TRPM4 (unknown origin) expressed in HEK293 cells assessed as reduction in intracellular Na+ influx after 45 mins by ANG2 dye-based fluorescence assay	ic50	4.7000	uM
2-[[2-(2-chlorophenoxy)acetyl]amino]-4-(1,3-oxazol-2-yl)benzoic acid	1602016: Inhibition of Flag-tagged TRPM4 (unknown origin) expressed in HEK293 cells assessed as reduction in intracellular Na+ influx after 45 mins by ANG2 dye-based fluorescence assay	ic50	4.9000	uM
2-[[2-(2-chlorophenoxy)acetyl]amino]-4-thiophen-3-ylbenzoic acid	1602016: Inhibition of Flag-tagged TRPM4 (unknown origin) expressed in HEK293 cells assessed as reduction in intracellular Na+ influx after 45 mins by ANG2 dye-based fluorescence assay	ic50	5.9000	uM
[(1S,3S)-7-chloro-1-(3,5-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]methanol	1896974: Agonist activity at human TRPM4 expressed in CHO-K1 cells assessed as increase in relative fluorescence unit by measuring membrane potential by FLIPR assay	ec50	8.9125	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, affects cotreatment, decreases expression, increases abundance, increases expression (+1 more)	5
9-phenanthrol	increases activity, decreases activity, decreases reaction, increases expression	4
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	decreases expression, decreases reaction	2
Tobacco Smoke Pollution	decreases expression, decreases methylation	2
Ionomycin	affects cotreatment, increases activity	2
Particulate Matter	increases abundance, increases expression	2
aristolochic acid I	increases expression	1
tempol	decreases reaction, increases expression	1
bufotalin	decreases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	increases expression, affects cotreatment, affects localization	1
tris(2-butoxyethyl) phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
manganese chloride	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
dichloroacetonitrile	affects response to substance	1
entinostat	increases expression	1
monomethylarsonous acid	affects acetylation, affects methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Decitabine	decreases expression, decreases reaction	1
Arsenic Trioxide	increases expression, decreases reaction	1
Leflunomide	increases expression	1
Air Pollutants	increases abundance, increases expression	1

ChEMBL screening assays

14 unique, capped per target: 13 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3734574	Functional	Inhibition of TRPM4 (unknown origin) expressed in HEK293 cells assessed as effect on agonist-induced Ca2+ changes	Agents and methods for treating ischemic and other diseases
CHEMBL4134892	Binding	Inhibition of TRPM4 in human Jurkat T cells assessed as reduction in intracellular calcium flux at 500 nM within 60 mins by whole cell patch clamp electrophysiology method	Scalaradial Is a Potent Inhibitor of Transient Receptor Potential Melastatin 2 (TRPM2) Ion Channels. — J Nat Prod

Cellosaurus cell lines

9 cell lines: 8 induced pluripotent stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B5FC	MRIi003-A-3	Induced pluripotent stem cell	Male
CVCL_B5FD	MRIi003-A-4	Induced pluripotent stem cell	Male
CVCL_B5NM	PGPC3_23	Induced pluripotent stem cell	Male
CVCL_B5NN	PGPC3_66	Induced pluripotent stem cell	Male
CVCL_B5NP	PGPC3_75	Induced pluripotent stem cell	Male
CVCL_B5NQ	PGPC3_87	Induced pluripotent stem cell	Male
CVCL_B5NR	PGPC3_93	Induced pluripotent stem cell	Male
CVCL_D6IA	FAHXMUi001-A	Induced pluripotent stem cell	Female
CVCL_D9V1	Ubigene HEK293 TRPM4 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00702117	PHASE4	COMPLETED	Ajmaline Utilization in the Diagnosis and Treatment of Cardiac Arrhythmias
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00701077	PHASE3	TERMINATED	DAPERB 3,4-DiAminoPyridine and Electrophysiological Response in Brugada Syndrome
NCT00927732	PHASE3	TERMINATED	Hydroquinidine Versus Placebo in Patients With Brugada Syndrome
NCT00170183	PHASE3	COMPLETED	Brain Natriuretic Peptide (BNP) to Preserve Renal Function in Hospitalized Patients With Heart Failure
NCT00270387	PHASE3	COMPLETED	A Study of Short-Term Outcomes and Economic Impact For Patients With Worsening Congestive Heart Failure When Natrecor (Nesiritide) is Added to Standard-Care Therapy, Compared to Administration of Placebo With Standard-Care Therapy
NCT00321295	PHASE3	COMPLETED	Biventricular Pacing In Patients With Left Ventricular Dysfunction After Cardiovascular Surgery
NCT00483197	PHASE3	UNKNOWN	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Pivotal Trial
NCT00490321	PHASE3	UNKNOWN	VentrAssistTM LVAD for the Treatment of Advanced Heart Failure - Destination Therapy
NCT00626028	PHASE3	COMPLETED	Comparison of Inhaled Nitric Oxide and Oxygen in Participants Reactivity During Acute Pulmonary Vasodilator Testing
NCT01013714	PHASE3	UNKNOWN	Cardiac Sympathetic Denervation for Prevention of Ventricular Tachyarrhythmias
NCT01217827	PHASE3	COMPLETED	Implantable Cardioverter-Defibrillator Use in the VA System
NCT01648634	PHASE3	COMPLETED	Nebivolol for the Prevention of Left Ventricular Systolic Dysfunction in Patients With Duchenne Muscular Dystrophy
NCT02924285	PHASE3	COMPLETED	Catheter Ablation Versus Amiodarone for Therapy of Premature Ventricular Contractions in Patients With Structural Heart Disease
NCT03860935	PHASE3	COMPLETED	Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
NCT04166331	PHASE3	COMPLETED	Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion
NCT05175066	PHASE3	COMPLETED	Bisoprolol Administration to Prevent Anthracycline-induced Cardiotoxicity
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT06158698	PHASE3	RECRUITING	CMP-MYTHiC Trial and Registry - CardioMyoPathy With MYocarditis THerapy With Colchicine
NCT06563895	PHASE3	RECRUITING	Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant
NCT06846086	PHASE3	RECRUITING	Cardioprotective Effects of Melatonin in Patients With Cardiomyopathy
NCT07116473	PHASE3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)