Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU5A52J)

DOT Name	Gamma-aminobutyric acid type B receptor subunit 1 (GABBR1)
Synonyms	GABA-B receptor 1; GABA-B-R1; GABA-BR1; GABABR1; Gb1
Gene Name	GABBR1
Related Disease	Delirium ( ) Succinic semialdehyde dehydrogenase deficiency ( ) Acquired immune deficiency syndrome ( ) Alcohol use disorder ( ) Alzheimer disease ( ) Autism ( ) Cocaine addiction ( ) Coeliac disease ( ) Colorectal carcinoma ( ) Congestive heart failure ( ) Encephalitis ( ) Epilepsy ( ) Lung adenocarcinoma ( ) Major depressive disorder ( ) Methamphetamine dependence ( ) Mood disorder ( ) Myasthenia gravis ( ) Nasopharyngeal carcinoma ( ) Nicotine dependence ( ) Obsessive compulsive disorder ( ) Obstructive sleep apnea ( ) Pancreatic cancer ( ) Pancreatic tumour ( ) Panic disorder ( ) Prostate cancer ( ) Prostate carcinoma ( ) Rheumatoid arthritis ( ) Status epilepticus seizure ( ) Type-1 diabetes ( ) Eating disorder ( ) Small-cell lung cancer ( ) Essential tremor ( ) High blood pressure ( ) ACTH-independent macronodular adrenal hyperplasia 1 ( ) Lung cancer ( ) Parkinson disease ( ) Psoriatic arthritis ( ) Rett syndrome ( ) Systemic lupus erythematosus ( )
UniProt ID	GABR1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	4MQE; 4MQF; 4MR7; 4MR8; 4MR9; 4MRM; 4MS1; 4MS3; 4MS4; 4PAS; 6HKC; 6UO8; 6UO9; 6UOA; 6VJM; 6W2X; 6W2Y; 6WIV; 7C7Q; 7C7S; 7CA3; 7CA5; 7CUM; 7EB2
Pfam ID	PF00003 ; PF01094 ; PF00084
Sequence	MLLLLLLAPLFLRPPGAGGAQTPNATSEGCQIIHPPWEGGIRYRGLTRDQVKAINFLPVD YEIEYVCRGEREVVGPKVRKCLANGSWTDMDTPSRCVRICSKSYLTLENGKVFLTGGDLP ALDGARVDFRCDPDFHLVGSSRSICSQGQWSTPKPHCQVNRTPHSERRAVYIGALFPMSG GWPGGQACQPAVEMALEDVNSRRDILPDYELKLIHHDSKCDPGQATKYLYELLYNDPIKI ILMPGCSSVSTLVAEAARMWNLIVLSYGSSSPALSNRQRFPTFFRTHPSATLHNPTRVKL FEKWGWKKIATIQQTTEVFTSTLDDLEERVKEAGIEITFRQSFFSDPAVPVKNLKRQDAR IIVGLFYETEARKVFCEVYKERLFGKKYVWFLIGWYADNWFKIYDPSINCTVDEMTEAVE GHITTEIVMLNPANTRSISNMTSQEFVEKLTKRLKRHPEETGGFQEAPLAYDAIWALALA LNKTSGGGGRSGVRLEDFNYNNQTITDQIYRAMNSSSFEGVSGHVVFDASGSRMAWTLIE QLQGGSYKKIGYYDSTKDDLSWSKTDKWIGGSPPADQTLVIKTFRFLSQKLFISVSVLSS LGIVLAVVCLSFNIYNSHVRYIQNSQPNLNNLTAVGCSLALAAVFPLGLDGYHIGRNQFP FVCQARLWLLGLGFSLGYGSMFTKIWWVHTVFTKKEEKKEWRKTLEPWKLYATVGLLVGM DVLTLAIWQIVDPLHRTIETFAKEEPKEDIDVSILPQLEHCSSRKMNTWLGIFYGYKGLL LLLGIFLAYETKSVSTEKINDHRAVGMAIYNVAVLCLITAPVTMILSSQQDAAFAFASLA IVFSSYITLVVLFVPKMRRLITRGEWQSEAQDTMKTGSSTNNNEEEKSRLLEKENRELEK IIAEKEERVSELRHQLQSRQQLRSRRHPPTPPEPSGGLPRGPPEPPDRLSCDGSRVHLLY K
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. Calcium is required for high affinity binding to GABA. 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). Activated by (-)-baclofen, cgp27492 and blocked by phaclofen ; Isoform 1E may regulate the formation of functional GABBR1/GABBR2 heterodimers by competing for GABBR2 binding. This could explain the observation that certain small molecule ligands exhibit differential affinity for central versus peripheral sites.
Tissue Specificity	Highly expressed in brain . Weakly expressed in heart, small intestine and uterus. Isoform 1A: Mainly expressed in granular cell and molecular layer . Isoform 1B: Mainly expressed in Purkinje cells . Isoform 1E: Predominantly expressed in peripheral tissues as kidney, lung, trachea, colon, small intestine, stomach, bone marrow, thymus and mammary gland .
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

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Delirium	DIS2OKP1	Definitive	Genetic Variation	[1]
Succinic semialdehyde dehydrogenase deficiency	DISVYC3M	Definitive	Biomarker	[2]
Acquired immune deficiency syndrome	DISL5UOX	Strong	Genetic Variation	[3]
Alcohol use disorder	DISMB65Y	Strong	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[5]
Autism	DISV4V1Z	Strong	Biomarker	[6]
Cocaine addiction	DISHTRXG	Strong	Biomarker	[4]
Coeliac disease	DISIY60C	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[9]
Encephalitis	DISLD1RL	Strong	Biomarker	[10]
Epilepsy	DISBB28L	Strong	Biomarker	[11]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[12]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[13]
Methamphetamine dependence	DIS1UU1B	Strong	Biomarker	[14]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[15]
Myasthenia gravis	DISELRCI	Strong	Genetic Variation	[16]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[17]
Nicotine dependence	DISZD9W7	Strong	Biomarker	[18]
Obsessive compulsive disorder	DIS1ZMM2	Strong	Biomarker	[19]
Obstructive sleep apnea	DIS0SVD1	Strong	Genetic Variation	[20]
Pancreatic cancer	DISJC981	Strong	Biomarker	[21]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[21]
Panic disorder	DISD3VNY	Strong	Genetic Variation	[22]
Prostate cancer	DISF190Y	Strong	Biomarker	[23]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[23]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[24]
Status epilepticus seizure	DISY3BIC	Strong	Biomarker	[25]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[26]
Eating disorder	DISVGXN0	moderate	Biomarker	[27]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[28]
Essential tremor	DIS7GBKQ	Disputed	Genetic Variation	[29]
High blood pressure	DISY2OHH	Disputed	Biomarker	[30]
ACTH-independent macronodular adrenal hyperplasia 1	DISH2YV8	Limited	Genetic Variation	[31]
Lung cancer	DISCM4YA	Limited	Genetic Variation	[32]
Parkinson disease	DISQVHKL	Limited	Biomarker	[33]
Psoriatic arthritis	DISLWTG2	Limited	Genetic Variation	[34]
Rett syndrome	DISGG5UV	Limited	Biomarker	[35]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[36]
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⏷ Show the Full List of 39 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

6 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 1 (GABBR1).	[37]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Gamma-aminobutyric acid type B receptor subunit 1 (GABBR1).	[38]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Gamma-aminobutyric acid type B receptor subunit 1 (GABBR1).	[39]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Gamma-aminobutyric acid type B receptor subunit 1 (GABBR1).	[41]
GSK683699	DMTW79H	Phase 2	GSK683699 increases the activity of Gamma-aminobutyric acid type B receptor subunit 1 (GABBR1).	[43]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Gamma-aminobutyric acid type B receptor subunit 1 (GABBR1).	[45]
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⏷ Show the Full List of 6 Drug(s)

4 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 1 (GABBR1).	[40]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Gamma-aminobutyric acid type B receptor subunit 1 (GABBR1).	[42]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Gamma-aminobutyric acid type B receptor subunit 1 (GABBR1).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Gamma-aminobutyric acid type B receptor subunit 1 (GABBR1).	[42]
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References

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