Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXPEDOK)

DOT Name Pannexin-1 (PANX1)
Synonyms PANX1
Gene Name PANX1
Related Disease
Arthritis ( )
Colitis ( )
Inflammatory bowel disease ( )
T-cell acute lymphoblastic leukaemia ( )
Acute liver failure ( )
Advanced cancer ( )
Anxiety ( )
Anxiety disorder ( )
Arteriosclerosis ( )
Atherosclerosis ( )
Autosomal recessive polycystic kidney disease ( )
Behcet disease ( )
Breast cancer ( )
Breast carcinoma ( )
Chagas disease ( )
Crohn disease ( )
Depression ( )
Duchenne muscular dystrophy ( )
Epilepsy ( )
Hepatocellular carcinoma ( )
HIV infectious disease ( )
Hypothyroidism ( )
Metastatic malignant neoplasm ( )
Migraine disorder ( )
Multiple sclerosis ( )
Neoplasm ( )
Nervous system inflammation ( )
Neuralgia ( )
Non-insulin dependent diabetes ( )
Obesity ( )
Obstructive sleep apnea ( )
Oocyte maturation defect 7 ( )
Polyp ( )
Stroke ( )
Ulcerative colitis ( )
Keratitis ( )
Rhabdomyosarcoma ( )
Testicular cancer ( )
Amyotrophic lateral sclerosis ( )
Malaria ( )
Melanoma ( )
Subarachnoid hemorrhage ( )
Temporal lobe epilepsy ( )
Type-1 diabetes ( )
Type-1/2 diabetes ( )
Venous thromboembolism ( )
UniProt ID
PANX1_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
6LTN; 6LTO; 6M02; 6M66; 6M67; 6M68; 6V6D; 6WBF; 6WBG; 6WBI; 6WBK; 6WBL; 6WBM; 6WBN; 7DWB; 7F8J; 7F8N; 7F8O; 7WSV
Pfam ID
PF00876
Sequence
MAIAQLATEYVFSDFLLKEPTEPKFKGLRLELAVDKMVTCIAVGLPLLLISLAFAQEISI
GTQISCFSPSSFSWRQAAFVDSYCWAAVQQKNSLQSESGNLPLWLHKFFPYILLLFAILL
YLPPLFWRFAAAPHICSDLKFIMEELDKVYNRAIKAAKSARDLDMRDGACSVPGVTENLG
QSLWEVSESHFKYPIVEQYLKTKKNSNNLIIKYISCRLLTLIIILLACIYLGYYFSLSSL
SDEFVCSIKSGILRNDSTVPDQFQCKLIAVGIFQLLSVINLVVYVLLAPVVVYTLFVPFR
QKTDVLKVYEILPTFDVLHFKSEGYNDLSLYNLFLEENISEVKSYKCLKVLENIKSSGQG
IDPMLLLTNLGMIKMDVVDGKTPMSAEMREEQGNQTAELQGMNIDSETKANNGEKNARQR
LLDSSC
Function
Ion channel involved in a variety of physiological functions such as blood pressure regulation, apoptotic cell clearance and oogenesis. Forms anion-selective channels with relatively low conductance and an order of permeabilities: nitrate>iodide>chlroride>>aspartate=glutamate=gluconate. Can release ATP upon activation through phosphorylation or cleavage at C-terminus. May play a role as a Ca(2+)-leak channel to regulate ER Ca(2+) homeostasis ; [Caspase-activated pannexin-1]: During apoptosis, the C terminal tail is cleaved by caspases, which opens the main pore acting as a large-pore ATP efflux channel with a broad distribution, which allows the regulated release of molecules and ions smaller than 1 kDa, such as nucleotides ATP and UTP, and selective plasma membrane permeability to attract phagocytes that engulf the dying cells.
Tissue Specificity Widely expressed . Highest expression is observed in oocytes and brain . Detected at very low levels in sperm cells .
KEGG Pathway
Efferocytosis (hsa04148 )
NOD-like receptor sig.ling pathway (hsa04621 )
Reactome Pathway
The NLRP3 inflammasome (R-HSA-844456 )
Electric Transmission Across Gap Junctions (R-HSA-112303 )

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Arthritis DIST1YEL Definitive Biomarker [1]
Colitis DISAF7DD Definitive Genetic Variation [2]
Inflammatory bowel disease DISGN23E Definitive Biomarker [3]
T-cell acute lymphoblastic leukaemia DIS17AI2 Definitive Biomarker [4]
Acute liver failure DIS5EZKX Strong Biomarker [5]
Advanced cancer DISAT1Z9 Strong Biomarker [6]
Anxiety DISIJDBA Strong Altered Expression [7]
Anxiety disorder DISBI2BT Strong Altered Expression [7]
Arteriosclerosis DISK5QGC Strong Biomarker [8]
Atherosclerosis DISMN9J3 Strong Biomarker [8]
Autosomal recessive polycystic kidney disease DISPUS40 Strong Biomarker [9]
Behcet disease DISSYMBS Strong Altered Expression [10]
Breast cancer DIS7DPX1 Strong Altered Expression [11]
Breast carcinoma DIS2UE88 Strong Altered Expression [11]
Chagas disease DIS8KNVF Strong Biomarker [12]
Crohn disease DIS2C5Q8 Strong Altered Expression [13]
Depression DIS3XJ69 Strong Biomarker [7]
Duchenne muscular dystrophy DISRQ3NV Strong Altered Expression [14]
Epilepsy DISBB28L Strong Biomarker [15]
Hepatocellular carcinoma DIS0J828 Strong Altered Expression [16]
HIV infectious disease DISO97HC Strong Biomarker [17]
Hypothyroidism DISR0H6D Strong Genetic Variation [18]
Metastatic malignant neoplasm DIS86UK6 Strong Biomarker [19]
Migraine disorder DISFCQTG Strong Biomarker [20]
Multiple sclerosis DISB2WZI Strong Biomarker [17]
Neoplasm DISZKGEW Strong Biomarker [16]
Nervous system inflammation DISB3X5A Strong Biomarker [17]
Neuralgia DISWO58J Strong Biomarker [21]
Non-insulin dependent diabetes DISK1O5Z Strong Biomarker [22]
Obesity DIS47Y1K Strong Biomarker [23]
Obstructive sleep apnea DIS0SVD1 Strong Biomarker [24]
Oocyte maturation defect 7 DISJZE7O Strong Autosomal dominant [25]
Polyp DISRSLYF Strong Biomarker [26]
Stroke DISX6UHX Strong Biomarker [27]
Ulcerative colitis DIS8K27O Strong Altered Expression [13]
Keratitis DISMFOEI moderate Biomarker [28]
Rhabdomyosarcoma DISNR7MS moderate Biomarker [29]
Testicular cancer DIS6HNYO moderate Biomarker [30]
Amyotrophic lateral sclerosis DISF7HVM Limited Biomarker [31]
Malaria DISQ9Y50 Limited Biomarker [32]
Melanoma DIS1RRCY Limited Altered Expression [33]
Subarachnoid hemorrhage DISI7I8Y Limited Altered Expression [34]
Temporal lobe epilepsy DISNOPXX Limited Genetic Variation [32]
Type-1 diabetes DIS7HLUB Limited Biomarker [35]
Type-1/2 diabetes DISIUHAP Limited Biomarker [36]
Venous thromboembolism DISUR7CR Limited Biomarker [37]
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⏷ Show the Full List of 46 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
13 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate affects the expression of Pannexin-1 (PANX1). [38]
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of Pannexin-1 (PANX1). [39]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of Pannexin-1 (PANX1). [40]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Pannexin-1 (PANX1). [41]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Pannexin-1 (PANX1). [42]
Cisplatin DMRHGI9 Approved Cisplatin increases the expression of Pannexin-1 (PANX1). [43]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide affects the expression of Pannexin-1 (PANX1). [44]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Pannexin-1 (PANX1). [38]
Phenobarbital DMXZOCG Approved Phenobarbital affects the expression of Pannexin-1 (PANX1). [45]
Adenosine triphosphate DM79F6G Approved Adenosine triphosphate decreases the activity of Pannexin-1 (PANX1). [46]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the expression of Pannexin-1 (PANX1). [47]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide decreases the expression of Pannexin-1 (PANX1). [48]
Formaldehyde DM7Q6M0 Investigative Formaldehyde increases the expression of Pannexin-1 (PANX1). [51]
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⏷ Show the Full List of 13 Drug(s)
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
TAK-243 DM4GKV2 Phase 1 TAK-243 decreases the sumoylation of Pannexin-1 (PANX1). [49]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of Pannexin-1 (PANX1). [50]
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References

1 Microglial pannexin-1 channel activation is a spinal determinant of joint pain.Sci Adv. 2018 Aug 8;4(8):eaas9846. doi: 10.1126/sciadv.aas9846. eCollection 2018 Aug.
2 Protective Effect of Methane-Rich Saline on Acetic Acid-Induced Ulcerative Colitis via Blocking the TLR4/NF-B/MAPK Pathway and Promoting IL-10/JAK1/STAT3-Mediated Anti-inflammatory Response.Oxid Med Cell Longev. 2019 Apr 28;2019:7850324. doi: 10.1155/2019/7850324. eCollection 2019.
3 Blockade of Pannexin-1 Channels and Purinergic P2X7 Receptors Shows Protective Effects Against Cytokines-Induced Colitis of Human Colonic Mucosa.Front Pharmacol. 2018 Aug 6;9:865. doi: 10.3389/fphar.2018.00865. eCollection 2018.
4 Chemotherapeutic drugs induce ATP release via caspase-gated pannexin-1 channels and a caspase/pannexin-1-independent mechanism.J Biol Chem. 2014 Sep 26;289(39):27246-27263. doi: 10.1074/jbc.M114.590240. Epub 2014 Aug 11.
5 Protective effect of genetic deletion of pannexin1 in experimental mouse models of acute and chronic liver disease.Biochim Biophys Acta Mol Basis Dis. 2018 Mar;1864(3):819-830. doi: 10.1016/j.bbadis.2017.12.013. Epub 2017 Dec 12.
6 Cancer metabolism in a snapshot: MRS(I).NMR Biomed. 2019 Oct;32(10):e4054. doi: 10.1002/nbm.4054. Epub 2019 Jan 11.
7 Pannexin-1 channel dysfunction in the medial prefrontal cortex mediates depressive-like behaviors induced by chronic social defeat stress and administration of mefloquine in mice.Neuropharmacology. 2018 Jul 15;137:256-267. doi: 10.1016/j.neuropharm.2017.12.004. Epub 2017 Dec 6.
8 Pannexin1 links lymphatic function to lipid metabolism and atherosclerosis.Sci Rep. 2017 Oct 20;7(1):13706. doi: 10.1038/s41598-017-14130-4.
9 Knockout of P2rx7 purinergic receptor attenuates cyst growth in a rat model of ARPKD.Am J Physiol Renal Physiol. 2019 Dec 1;317(6):F1649-F1655. doi: 10.1152/ajprenal.00395.2019. Epub 2019 Oct 21.
10 Low levels of pannexin-1 in Behet's syndrome.Int J Rheum Dis. 2019 Aug;22(8):1474-1478. doi: 10.1111/1756-185X.13614. Epub 2019 Jun 18.
11 Pannexin1 Is Associated with Enhanced Epithelial-To-Mesenchymal Transition in Human Patient Breast Cancer Tissues and in Breast Cancer Cell Lines.Cancers (Basel). 2019 Dec 7;11(12):1967. doi: 10.3390/cancers11121967.
12 Trypanosoma cruzi Infection Induces Pannexin-1 Channel Opening in Cardiac Myocytes.Am J Trop Med Hyg. 2018 Jan;98(1):105-112. doi: 10.4269/ajtmh.17-0293.
13 Expression and localization of pannexin-1 hemichannels in human colon in health and disease.Neurogastroenterol Motil. 2013 Jun;25(6):e395-405. doi: 10.1111/nmo.12130. Epub 2013 Apr 17.
14 Expression of Pannexin 1 and Pannexin 3 during skeletal muscle development, regeneration, and Duchenne muscular dystrophy.J Cell Physiol. 2018 Oct;233(10):7057-7070. doi: 10.1002/jcp.26629. Epub 2018 May 10.
15 Pannexin-1 channels in epilepsy.Neurosci Lett. 2019 Mar 16;695:71-75. doi: 10.1016/j.neulet.2017.09.004. Epub 2017 Sep 5.
16 Panx1 promotes invasion-metastasis cascade in hepatocellular carcinoma.J Cancer. 2019 Sep 7;10(23):5681-5688. doi: 10.7150/jca.32986. eCollection 2019.
17 Pannexin1 Channels Are Required for Chemokine-Mediated Migration of CD4+ T Lymphocytes: Role in Inflammation and Experimental Autoimmune Encephalomyelitis.J Immunol. 2016 May 15;196(10):4338-47. doi: 10.4049/jimmunol.1502440. Epub 2016 Apr 13.
18 Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
19 Loss of pannexin 1 attenuates melanoma progression by reversion to a melanocytic phenotype.J Biol Chem. 2012 Aug 17;287(34):29184-93. doi: 10.1074/jbc.M112.377176. Epub 2012 Jun 29.
20 Gap junctions, pannexins and pain.Neurosci Lett. 2019 Mar 16;695:46-52. doi: 10.1016/j.neulet.2017.06.035. Epub 2017 Jun 22.
21 Hematopoietic pannexin 1 function is critical for neuropathic pain.Sci Rep. 2017 Feb 14;7:42550. doi: 10.1038/srep42550.
22 Pannexin-1 mediated ATP release in adipocytes is sensitive to glucose and insulin and modulates lipolysis and macrophage migration.Acta Physiol (Oxf). 2020 Feb;228(2):e13360. doi: 10.1111/apha.13360. Epub 2019 Oct 14.
23 Pannexin 1 regulates adipose stromal cell differentiation and fat accumulation.Sci Rep. 2018 Nov 1;8(1):16166. doi: 10.1038/s41598-018-34234-9.
24 Evidence that 5-HT stimulates intracellular Ca(2+) signalling and activates pannexin-1 currents in type II cells of the rat carotid body.J Physiol. 2017 Jul 1;595(13):4261-4277. doi: 10.1113/JP273473. Epub 2017 Apr 25.
25 A pannexin 1 channelopathy causes human oocyte death. Sci Transl Med. 2019 Mar 27;11(485):eaav8731. doi: 10.1126/scitranslmed.aav8731.
26 Decreased ciliary beat responsiveness to acetylcholine in the nasal polyp epithelium.Clin Otolaryngol. 2019 May;44(3):356-365. doi: 10.1111/coa.13312. Epub 2019 Mar 18.
27 Pannexin1 knockout and blockade reduces ischemic stroke injury in female, but not in male mice.Oncotarget. 2017 Jun 6;8(23):36973-36983. doi: 10.18632/oncotarget.16937.
28 Pannexin 1 Channels Contribute to IL-1 Expression via NLRP3/Caspase-1 Inflammasome in Aspergillus Fumigatus Keratitis.Curr Eye Res. 2019 Jul;44(7):716-725. doi: 10.1080/02713683.2019.1584321. Epub 2019 Mar 29.
29 Pannexin 1 inhibits rhabdomyosarcoma progression through a mechanism independent of its canonical channel function.Oncogenesis. 2018 Nov 21;7(11):89. doi: 10.1038/s41389-018-0100-4.
30 In vitro effect of Pannexin 1 channel on the invasion and migration of I-10 testicular cancer cells via ERK1/2 signaling pathway.Biomed Pharmacother. 2019 Sep;117:109090. doi: 10.1016/j.biopha.2019.109090. Epub 2019 Jun 12.
31 Downregulated Glia Interplay and Increased miRNA-155 as Promising Markers to Track ALS at anEarly Stage.Mol Neurobiol. 2018 May;55(5):4207-4224. doi: 10.1007/s12035-017-0631-2. Epub 2017 Jun 13.
32 Pannexin-1 channels contribute to seizure generation in human epileptic brain tissue and in a mouse model of epilepsy.Sci Transl Med. 2018 May 30;10(443):eaar3796. doi: 10.1126/scitranslmed.aar3796.
33 Inhibition of Pannexin 1 Reduces the Tumorigenic Properties of Human Melanoma Cells.Cancers (Basel). 2019 Jan 16;11(1):102. doi: 10.3390/cancers11010102.
34 Roles of Pannexin-1 Channels in Inflammatory Response through the TLRs/NF-Kappa B Signaling Pathway Following Experimental Subarachnoid Hemorrhage in Rats.Front Mol Neurosci. 2017 Jun 6;10:175. doi: 10.3389/fnmol.2017.00175. eCollection 2017.
35 Pannexin-2-deficiency sensitizes pancreatic -cells to cytokine-induced apoptosis invitro and impairs glucose tolerance invivo.Mol Cell Endocrinol. 2017 Jun 15;448:108-121. doi: 10.1016/j.mce.2017.04.001. Epub 2017 Apr 5.
36 The P2X7 receptor and pannexin-1 are involved in glucose-induced autocrine regulation in -cells.Sci Rep. 2018 Jun 12;8(1):8926. doi: 10.1038/s41598-018-27281-9.
37 Selective inhibition of Panx1 channels decreases hemostasis and thrombosis in vivo.Thromb Res. 2019 Nov;183:56-62. doi: 10.1016/j.thromres.2019.09.028. Epub 2019 Oct 18.
38 Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
39 Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
40 Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
41 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
42 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
43 Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
44 Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
45 Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
46 Pharmacological characterization of pannexin-1 currents expressed in mammalian cells. J Pharmacol Exp Ther. 2009 Feb;328(2):409-18. doi: 10.1124/jpet.108.146365. Epub 2008 Nov 20.
47 New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
48 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
49 Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
50 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
51 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.