Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7MPSG7)

• DOT Name: Rhodopsin kinase GRK1 (GRK1)
• Synonyms: RK; EC 2.7.11.14; G protein-coupled receptor kinase 1
• Gene Name: GRK1
• Related Disease:
  Cardiac failure
  Congestive heart failure
  Oguchi disease
  Oguchi disease-2
  Enhanced S-cone syndrome
  Leber congenital amaurosis 12
  Melanoma
  Neuralgia
  Retinitis pigmentosa
  Congenital stationary night blindness
  Encephalitis
  Retinopathy
  Leber congenital amaurosis 1
  Rheumatoid arthritis
• UniProt ID: GRK1_HUMAN
• PDB ID: 5AFP
• EC Number: 2.7.11.14
• Pfam ID: PF00069 ; PF00615
• Sequence:
  MDFGSLETVVANSAFIAARGSFDGSSSQPSRDKKYLAKLKLPPLSKCESLRDSLSLEFES
  VCLEQPIGKKLFQQFLQSAEKHLPALELWKDIEDYDTADNDLQPQKAQTILAQYLDPQAK
  LFCSFLDEGIVAKFKEGPVEIQDGLFQPLLQATLAHLGQAPFQEYLGSLYFLRFLQWKWL
  EAQPMGEDWFLDFRVLGKGGFGEVSACQMKATGKLYACKKLNKKRLKKRKGYQGAMVEKK
  ILMKVHSRFIVSLAYAFETKADLCLVMTIMNGGDIRYHIYNVNEENPGFPEPRALFYTAQ
  IICGLEHLHQRRIVYRDLKPENVLLDNDGNVRISDLGLAVELLDGQSKTKGYAGTPGFMA
  PELLQGEEYDFSVDYFALGVTLYEMIAARGPFRARGEKVENKELKHRIISEPVKYPDKFS
  QASKDFCEALLEKDPEKRLGFRDETCDKLRAHPLFKDLNWRQLEAGMLMPPFIPDSKTVY
  AKDIQDVGAFSTVKGVAFDKTDTEFFQEFATGNCPIPWQEEMIETGIFGELNVWRSDGQM
  PDDMKGISGGSSSSSKSGMCLVS
• Function: Retina-specific kinase involved in the signal turnoff via phosphorylation of rhodopsin (RHO), the G protein- coupled receptor that initiates the phototransduction cascade. This rapid desensitization is essential for scotopic vision and permits rapid adaptation to changes in illumination. May play a role in the maintenance of the outer nuclear layer in the retina.
• Tissue Specificity: Retinal-specific. Expressed in rods and cones cells.
• KEGG Pathway:
  Chemokine sig.ling pathway (hsa04062)
  Endocytosis (hsa04144)
  Phototransduction (hsa04744)
• Reactome Pathway: Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Definitive	Biomarker	[1]
Congestive heart failure	DIS32MEA	Definitive	Biomarker	[1]
Oguchi disease	DISLYKY5	Definitive	Autosomal recessive	[2]
Oguchi disease-2	DIS1N8MZ	Definitive	Autosomal recessive	[3]
Enhanced S-cone syndrome	DIS2IWS3	Strong	Biomarker	[4]
Leber congenital amaurosis 12	DIS0EIZY	Strong	Genetic Variation	[5]
Melanoma	DIS1RRCY	Strong	Altered Expression	[6]
Neuralgia	DISWO58J	Strong	Biomarker	[7]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[8]
Congenital stationary night blindness	DISX0CWK	moderate	Genetic Variation	[9]
Encephalitis	DISLD1RL	moderate	Biomarker	[10]
Retinopathy	DISB4B0F	moderate	Biomarker	[11]
Leber congenital amaurosis 1	DISY2B33	Limited	Genetic Variation	[12]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[13]

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 Rhodopsin kinase GRK1 (GRK1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Rhodopsin kinase GRK1 (GRK1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Rhodopsin kinase GRK1 (GRK1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Malathion	DMXZ84M	Approved	Malathion increases the expression of Rhodopsin kinase GRK1 (GRK1).	[16]

References

• [1] Ventricular hypertrophy plus neurohumoral activation is necessary to alter the cardiac beta-adrenoceptor system in experimental heart failure.Circ Res. 2002 Nov 29;91(11):1056-62. doi: 10.1161/01.res.0000045088.59360.b7.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] A novel homozygous GRK1 mutation (P391H) in 2 siblings with Oguchi disease with markedly reduced cone responses. Ophthalmology. 2007 Jan;114(1):134-41. doi: 10.1016/j.ophtha.2006.05.069. Epub 2006 Oct 27.
• [4] Cone deactivation kinetics and GRK1/GRK7 expression in enhanced S cone syndrome caused by mutations in NR2E3.Invest Ophthalmol Vis Sci. 2003 Mar;44(3):1268-74. doi: 10.1167/iovs.02-0494.
• [5] RD3 gene delivery restores guanylate cyclase localization and rescues photoreceptors in the Rd3 mouse model of Leber congenital amaurosis 12.Hum Mol Genet. 2013 Oct 1;22(19):3894-905. doi: 10.1093/hmg/ddt244. Epub 2013 Jun 4.
• [6] Photoreceptor proteins as cancer-retina antigens.Int J Cancer. 2007 Mar 15;120(6):1268-76. doi: 10.1002/ijc.22458.
• [7] Identification of candidate genes and miRNAs associated with neuropathic pain induced by spared nerve injury.Int J Mol Med. 2019 Oct;44(4):1205-1218. doi: 10.3892/ijmm.2019.4305. Epub 2019 Aug 6.
• [8] Toxicology and Pharmacology of an AAV Vector Expressing Codon-Optimized RPGR in RPGR-Deficient Rd9 Mice.Hum Gene Ther Clin Dev. 2018 Dec;29(4):188-197. doi: 10.1089/humc.2018.168.
• [9] Biochemical evidence for pathogenicity of rhodopsin kinase mutations correlated with the oguchi form of congenital stationary night blindness.Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2824-7. doi: 10.1073/pnas.95.6.2824.
• [10] Rho-mediated regulation of tight junctions during monocyte migration across the blood-brain barrier in HIV-1 encephalitis (HIVE).Blood. 2006 Jun 15;107(12):4770-80. doi: 10.1182/blood-2005-11-4721. Epub 2006 Feb 14.
• [11] Low expression of alphaA-crystallins and rhodopsin kinase of photoreceptors in retinal dystrophy rat.Invest Ophthalmol Vis Sci. 1999 Nov;40(12):2788-94.
• [12] Combined rod and cone transduction by adeno-associated virus 2/8.Hum Gene Ther. 2013 Dec;24(12):982-92. doi: 10.1089/hum.2013.154. Epub 2013 Oct 30.
• [13] Decreased expression and activity of G-protein-coupled receptor kinases in peripheral blood mononuclear cells of patients with rheumatoid arthritis.FASEB J. 1999 Apr;13(6):715-25. doi: 10.1096/fasebj.13.6.715.
• [14] 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.
• [15] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [16] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [17] 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.