Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT05Y9ZR)

• DOT Name: Glycine receptor subunit alpha-1 (GLRA1)
• Synonyms: Glycine receptor 48 kDa subunit; Glycine receptor strychnine-binding subunit
• Gene Name: GLRA1
• Related Disease:
  Hyperekplexia 1
  Hereditary hyperekplexia
• UniProt ID: GLRA1_HUMAN
• PDB ID: 1MOT; 1VRY; 2M6B; 2M6I; 4X5T; 8DN2; 8DN3; 8DN4; 8DN5
• Pfam ID: PF02931 ; PF02932
• Sequence:
  MYSFNTLRLYLWETIVFFSLAASKEAEAARSAPKPMSPSDFLDKLMGRTSGYDARIRPNF
  KGPPVNVSCNIFINSFGSIAETTMDYRVNIFLRQQWNDPRLAYNEYPDDSLDLDPSMLDS
  IWKPDLFFANEKGAHFHEITTDNKLLRISRNGNVLYSIRITLTLACPMDLKNFPMDVQTC
  IMQLESFGYTMNDLIFEWQEQGAVQVADGLTLPQFILKEEKDLRYCTKHYNTGKFTCIEA
  RFHLERQMGYYLIQMYIPSLLIVILSWISFWINMDAAPARVGLGITTVLTMTTQSSGSRA
  SLPKVSYVKAIDIWMAVCLLFVFSALLEYAAVNFVSRQHKELLRFRRKRRHHKSPMLNLF
  QEDEAGEGRFNFSAYGMGPACLQAKDGISVKGANNSNTTNPPPAPSKSPEEMRKLFIQRA
  KKIDKISRIGFPMAFLIFNMFYWIIYKIVRREDVHNQ
• Function: Glycine receptors are ligand-gated chloride channels. Channel opening is triggered by extracellular glycine. Channel opening is also triggered by taurine and beta-alanine. Channel characteristics depend on the subunit composition; heteropentameric channels are activated by lower glycine levels and display faster desensitization. Plays an important role in the down-regulation of neuronal excitability. Contributes to the generation of inhibitory postsynaptic currents. Channel activity is potentiated by ethanol. Potentiation of channel activity by intoxicating levels of ethanol contribute to the sedative effects of ethanol.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway: Neurotransmitter receptors and postsynaptic signal transmission (R-HSA-112314)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperekplexia 1	DISRXUL0	Definitive	Autosomal recessive	[1]
Hereditary hyperekplexia	DIS9YXFE	Supportive	Autosomal dominant	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Sevoflurane	DMC9O43	Approved	Glycine receptor subunit alpha-1 (GLRA1) increases the Nerve injury ADR of Sevoflurane.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Glycine receptor subunit alpha-1 (GLRA1).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Glycine receptor subunit alpha-1 (GLRA1).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin increases the activity of Glycine receptor subunit alpha-1 (GLRA1).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the activity of Glycine receptor subunit alpha-1 (GLRA1).	[5]
Lindane	DMB8CNL	Approved	Lindane decreases the activity of Glycine receptor subunit alpha-1 (GLRA1).	[6]
Glycine	DMIOZ29	Approved	Glycine increases the activity of Glycine receptor subunit alpha-1 (GLRA1).	[7]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the activity of Glycine receptor subunit alpha-1 (GLRA1).	[5]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Glycine receptor subunit alpha-1 (GLRA1).	[9]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the activity of Glycine receptor subunit alpha-1 (GLRA1).	[10]

References

• [1] C.292G>A, a novel glycine receptor alpha 1 subunit gene (GLRA1) mutation found in a Chinese patient with hyperekplexia: A case report. Medicine (Baltimore). 2020 Apr;99(17):e19968. doi: 10.1097/MD.0000000000019968.
• [2] Hereditary Hyperekplexia Overview. 2007 Jul 31 [updated 2019 Dec 19]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] 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.
• [4] A mouse line for inducible and reversible silencing of specific neurons. Mol Brain. 2014 Sep 18;7:68. doi: 10.1186/s13041-014-0068-8.
• [5] Synergistic inhibition of glycinergic transmission in vitro and in vivo by flavonoids and strychnine. Toxicol Sci. 2010 Nov;118(1):171-82. doi: 10.1093/toxsci/kfq245. Epub 2010 Aug 18.
• [6] Mechanism of action of the insecticides, lindane and fipronil, on glycine receptor chloride channels. Br J Pharmacol. 2012 Apr;165(8):2707-20. doi: 10.1111/j.1476-5381.2011.01722.x.
• [7] Sarcophine and (7S, 8R)-dihydroxydeepoxysarcophine from the Red Sea soft coral Sarcophyton glaucum as in vitro and in vivo modulators of glycine receptors. Neurotoxicology. 2020 Sep;80:105-111. doi: 10.1016/j.neuro.2020.07.002. Epub 2020 Jul 20.
• [8] 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.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [10] Does acetaldehyde mediate ethanol action in the central nervous system?. Alcohol Clin Exp Res. 2001 Nov;25(11):1570-5.
• [11] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.