Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT67RIFY)

• DOT Name: Gamma-aminobutyric acid type B receptor subunit 2 (GABBR2)
• Synonyms: GABA-B receptor 2; GABA-B-R2; GABA-BR2; GABABR2; Gb2; G-protein coupled receptor 51; HG20
• Gene Name: GABBR2
• Related Disease:
  Autism
  Developmental and epileptic encephalopathy, 59
  Hereditary sensory and autonomic neuropathy type 1
  Huntington disease
  Major depressive disorder
  Neurodevelopmental disorder
  Neurodevelopmental disorder with poor language and loss of hand skills
  Rett syndrome
  Rheumatoid arthritis
  Atypical Rett syndrome
  Advanced cancer
  Lung adenocarcinoma
  Schizophrenia
  Temporal lobe epilepsy
• UniProt ID: GABR2_HUMAN
• PDB ID: 4F11; 4F12; 4MQE; 4MQF; 4MR7; 4MR8; 4MR9; 4MRM; 4MS1; 4MS3; 4MS4; 4PAS; 6M8R; 6OCP; 6UO8; 6UO9; 6UOA; 6VJM; 6W2X; 6WIV; 7C7Q; 7C7S; 7CA3; 7CA5; 7CUM; 7EB2
• Pfam ID: PF00003 ; PF01094 ; PF18455
• Sequence:
  MASPRSSGQPGPPPPPPPPPARLLLLLLLPLLLPLAPGAWGWARGAPRPPPSSPPLSIMG
  LMPLTKEVAKGSIGRGVLPAVELAIEQIRNESLLRPYFLDLRLYDTECDNAKGLKAFYDA
  IKYGPNHLMVFGGVCPSVTSIIAESLQGWNLVQLSFAATTPVLADKKKYPYFFRTVPSDN
  AVNPAILKLLKHYQWKRVGTLTQDVQRFSEVRNDLTGVLYGEDIEISDTESFSNDPCTSV
  KKLKGNDVRIILGQFDQNMAAKVFCCAYEENMYGSKYQWIIPGWYEPSWWEQVHTEANSS
  RCLRKNLLAAMEGYIGVDFEPLSSKQIKTISGKTPQQYEREYNNKRSGVGPSKFHGYAYD
  GIWVIAKTLQRAMETLHASSRHQRIQDFNYTDHTLGRIILNAMNETNFFGVTGQVVFRNG
  ERMGTIKFTQFQDSREVKVGEYNAVADTLEIINDTIRFQGSEPPKDKTIILEQLRKISLP
  LYSILSALTILGMIMASAFLFFNIKNRNQKLIKMSSPYMNNLIILGGMLSYASIFLFGLD
  GSFVSEKTFETLCTVRTWILTVGYTTAFGAMFAKTWRVHAIFKNVKMKKKIIKDQKLLVI
  VGGMLLIDLCILICWQAVDPLRRTVEKYSMEPDPAGRDISIRPLLEHCENTHMTIWLGIV
  YAYKGLLMLFGCFLAWETRNVSIPALNDSKYIGMSVYNVGIMCIIGAAVSFLTRDQPNVQ
  FCIVALVIIFCSTITLCLVFVPKLITLRTNPDAATQNRRFQFTQNQKKEDSKTSTSVTSV
  NQASTSRLEGLQSENHRLRMKITELDKDLEEVTMQLQDTPEKTTYIKQNHYQELNDILNL
  GNFTESTDGGKAILKNHLDQNPQLQWNTTEPSRTCKDPIEDINSPEHIQRRLSLQLPILH
  HAYLPSIGGVDASCVSPCVSPTASPRHRHVPPSFRVMVSGL
• Function: Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2. Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis. Plays a critical role in the fine-tuning of inhibitory synaptic transmission. Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials. Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception (Probable).
• Tissue Specificity: Highly expressed in brain, especially in cerebral cortex, thalamus, hippocampus, frontal, occipital and temporal lobe, occipital pole and cerebellum, followed by corpus callosum, caudate nucleus, spinal cord, amygdala and medulla . Weakly expressed in heart, testis and skeletal muscle .
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  GABAergic sy.pse (hsa04727)
  Taste transduction (hsa04742)
  Estrogen sig.ling pathway (hsa04915)
  GnRH secretion (hsa04929)
  Morphine addiction (hsa05032)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Class C/3 (Metabotropic glutamate/pheromone receptors) (R-HSA-420499)
  GABA B receptor activation (R-HSA-977444)
  Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits (R-HSA-997272)
  Activation of G protein gated Potassium channels (R-HSA-1296041)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Strong	Biomarker	[1]
Developmental and epileptic encephalopathy, 59	DISAZWJZ	Strong	Autosomal dominant	[2]
Hereditary sensory and autonomic neuropathy type 1	DISLSPO4	Strong	Biomarker	[3]
Huntington disease	DISQPLA4	Strong	Genetic Variation	[4]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[5]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[6]
Neurodevelopmental disorder with poor language and loss of hand skills	DISBO4QF	Strong	Autosomal dominant	[7]
Rett syndrome	DISGG5UV	Strong	Biomarker	[8]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[9]
Atypical Rett syndrome	DISWF699	Supportive	Autosomal dominant	[10]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[11]
Lung adenocarcinoma	DISD51WR	Limited	Biomarker	[11]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[12]
Temporal lobe epilepsy	DISNOPXX	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Gamma-aminobutyric acid type B receptor subunit 2 (GABBR2).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Gamma-aminobutyric acid type B receptor subunit 2 (GABBR2).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Gamma-aminobutyric acid type B receptor subunit 2 (GABBR2).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Gamma-aminobutyric acid type B receptor subunit 2 (GABBR2).	[17]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Gamma-aminobutyric acid type B receptor subunit 2 (GABBR2).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Gamma-aminobutyric acid type B receptor subunit 2 (GABBR2).	[20]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Gamma-aminobutyric acid type B receptor subunit 2 (GABBR2).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Gamma-aminobutyric acid type B receptor subunit 2 (GABBR2).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Gamma-aminobutyric acid type B receptor subunit 2 (GABBR2).	[25]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Gamma-aminobutyric acid type B receptor subunit 2 (GABBR2).	[26]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Gamma-aminobutyric acid type B receptor subunit 2 (GABBR2).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Gamma-aminobutyric acid type B receptor subunit 2 (GABBR2).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Gamma-aminobutyric acid type B receptor subunit 2 (GABBR2).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Gamma-aminobutyric acid type B receptor subunit 2 (GABBR2).	[24]

References

• [1] Expression of GABA(B) receptors is altered in brains of subjects with autism.Cerebellum. 2009 Mar;8(1):64-9. doi: 10.1007/s12311-008-0075-3.
• [2] Redistribution of GABAB(1) protein and atypical GABAB responses in GABAB(2)-deficient mice. J Neurosci. 2004 Jul 7;24(27):6086-97. doi: 10.1523/JNEUROSCI.5635-03.2004.
• [3] Cloning of a novel G-protein-coupled receptor GPR 51 resembling GABAB receptors expressed predominantly in nervous tissues and mapped proximal to the hereditary sensory neuropathy type 1 locus on chromosome 9.Genomics. 1999 Mar 15;56(3):288-95. doi: 10.1006/geno.1998.5706.
• [4] A GABBR2 gene variant modifies pathophysiology in Huntington's disease.Neurosci Lett. 2016 May 4;620:8-13. doi: 10.1016/j.neulet.2016.03.038. Epub 2016 Mar 23.
• [5] Expression of GABAA 2-, 1- and -receptors are altered significantly in the lateral cerebellum of subjects with schizophrenia, major depression and bipolar disorder.Transl Psychiatry. 2013 Sep 10;3(9):e303. doi: 10.1038/tp.2013.64.
• [6] Identification of novel genetic causes of Rett syndrome-like phenotypes. J Med Genet. 2016 Mar;53(3):190-9. doi: 10.1136/jmedgenet-2015-103568. Epub 2016 Jan 6.
• [7] De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet. 2014 Oct 2;95(4):360-70. doi: 10.1016/j.ajhg.2014.08.013. Epub 2014 Sep 25.
• [8] Reply to "a novel mutation in the transmembrane 6 domain of GABBR2 leads to a rett-like phenotype".Ann Neurol. 2018 Feb;83(2):439. doi: 10.1002/ana.25154.
• [9] Genome-wide association study of response to tumour necrosis factor inhibitor therapy in rheumatoid arthritis.Pharmacogenomics J. 2018 Sep;18(5):657-664. doi: 10.1038/s41397-018-0040-6. Epub 2018 Aug 31.
• [10] GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy. Ann Neurol. 2017 Sep;82(3):466-478. doi: 10.1002/ana.25032.
• [11] Genome-wide DNA Methylation Analysis Reveals GABBR2 as a Novel Epigenetic Target for EGFR 19 Deletion Lung Adenocarcinoma with Induction Erlotinib Treatment.Clin Cancer Res. 2017 Sep 1;23(17):5003-5014. doi: 10.1158/1078-0432.CCR-16-2688. Epub 2017 May 10.
• [12] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [13] Increased expression of gamma-aminobutyric acid type B receptors in the hippocampus of patients with temporal lobe epilepsy.Neurosci Lett. 2003 Dec 4;352(2):141-5. doi: 10.1016/j.neulet.2003.08.046.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [16] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [17] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [18] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [19] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [20] 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.
• [21] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [22] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [23] 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.
• [24] 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.
• [25] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [26] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [27] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.