Details of Drug Off-Target (DOT)

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

• DOT Name: Calcium homeostasis modulator protein 1 (CALHM1)
• Synonyms: Protein FAM26C
• Gene Name: CALHM1
• Related Disease:
  Epilepsy
  Prion disease
  Schizophrenia
  Temporal lobe epilepsy
  Urinary bladder cancer
  Urinary bladder neoplasm
  Stroke
  Cognitive impairment
• UniProt ID: CAHM1_HUMAN
• PDB ID: 8GMP; 8GMR; 8S8Z; 8S90
• Pfam ID: PF14798
• Sequence:
  MMDKFRMIFQFLQSNQESFMNGICGIMALASAQMYSAFDFNCPCLPGYNAAYSAGILLAP
  PLVLFLLGLVMNNNVSMLAEEWKRPLGRRAKDPAVLRYMFCSMAQRALIAPVVWVAVTLL
  DGKCFLCAFCTAVPVSALGNGSLAPGLPAPELARLLARVPCPEIYDGDWLLAREVAVRYL
  RCISQALGWSFVLLTTLLAFVVRSVRPCFTQAAFLKSKYWSHYIDIERKLFDETCTEHAK
  AFAKVCIQQFFEAMNHDLELGHTHGTLATAPASAAAPTTPDGAEEEREKLRGITDQGTMN
  RLLTSWHKCKPPLRLGQEEPPLMGNGWAGGGPRPPRKEVATYFSKV
• Function: Pore-forming subunit of a voltage-gated ion channel required for sensory perception of sweet, bitter and umami tastes. Specifically present in type II taste bud cells, where it plays a central role in sweet, bitter and umami taste perception by inducing ATP release from the cell, ATP acting as a neurotransmitter to activate afferent neural gustatory pathways. Together with CALHM3, forms a fast-activating voltage-gated ATP-release channel in type II taste bud cells (TBCs). Acts both as a voltage-gated and calcium-activated ion channel: mediates neuronal excitability in response to changes in extracellular Ca(2+) concentration. Has poor ion selectivity and forms a wide pore (around 14 Angstroms) that mediates permeation of Ca(2+), Na(+) and K(+), as well as permeation of monovalent anions. Acts as an activator of the ERK1 and ERK2 cascade. Triggers endoplasmic reticulum stress by reducing the calcium content of the endoplasmic reticulum. May indirectly control amyloid precursor protein (APP) proteolysis and aggregated amyloid-beta (Abeta) peptides levels in a Ca(2+) dependent manner.
• Tissue Specificity: Predominantly expressed in adult brain. Detected also in retinoic acid-differentiated SH-SY5Y cells. Specifically expressed in circumvallate taste bud cells.
• KEGG Pathway: Taste transduction (hsa04742)
• Reactome Pathway:
  Sensory perception of salty taste (R-HSA-9730628)
  Sensory perception of sweet, bitter, and umami (glutamate) taste (R-HSA-9717207)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Strong	Biomarker	[1]
Prion disease	DISOUMB0	Strong	Biomarker	[2]
Schizophrenia	DISSRV2N	Strong	Biomarker	[3]
Temporal lobe epilepsy	DISNOPXX	Strong	Genetic Variation	[4]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[5]
Stroke	DISX6UHX	moderate	Genetic Variation	[6]
Cognitive impairment	DISH2ERD	Limited	Biomarker	[7]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Calcium homeostasis modulator protein 1 (CALHM1).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Calcium homeostasis modulator protein 1 (CALHM1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Calcium homeostasis modulator protein 1 (CALHM1).	[11]

1 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Calcium homeostasis modulator protein 1 (CALHM1).	[9]

References

• [1] A polymorphism in CALHM1 is associated with temporal lobe epilepsy.Epilepsy Behav. 2011 Apr;20(4):681-5. doi: 10.1016/j.yebeh.2011.02.007. Epub 2011 Mar 24.
• [2] Genetic variability of the gene cluster CALHM 1-3 in sporadic Creutzfeldt-Jakob disease.Prion. 2012 Sep-Oct;6(4):407-12. doi: 10.4161/pri.20785. Epub 2012 Aug 9.
• [3] Two-stage replication of previous genome-wide association studies of AS3MT-CNNM2-NT5C2 gene cluster region in a large schizophrenia case-control sample from Han Chinese population.Schizophr Res. 2016 Oct;176(2-3):125-130. doi: 10.1016/j.schres.2016.07.004. Epub 2016 Jul 8.
• [4] No association between polymorphisms in the calcium homeostasis modulator 1 gene and mesial temporal lobe epilepsy risk in a Chinese population.Seizure. 2014 Mar;23(3):231-3. doi: 10.1016/j.seizure.2013.11.010. Epub 2013 Nov 23.
• [5] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [6] No association between CALHM1 polymorphism and Alzheimer's disease risk in a Hungarian population.Psychiatr Genet. 2011 Oct;21(5):249-52. doi: 10.1097/YPG.0b013e3283457bcc.
• [7] CALHM1 P86L polymorphism does not alter amyloid-beta or tau in cerebrospinal fluid.Neurosci Lett. 2010 Jan 22;469(2):265-7. doi: 10.1016/j.neulet.2009.12.011. Epub 2009 Dec 23.
• [8] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [10] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [11] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.