Target Information

Target General Infomation
Target ID
T42446
Former ID
TTDS00022
Target Name
Gamma-aminobutyric acid B receptor
Gene Name
GABBR2
Synonyms
GABA B receptor; GABA(B) receptor; GABAB receptor; Gamma-aminobutyric acid type b receptor; GABBR2
Target Type
Successful
Disease Anxiety disorder [ICD9: 300, 311; ICD10: F32, F40-F42]
Absence seizures [ICD10: G40]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Depression [ICD9: 311; ICD10: F30-F39]
Drug abuse [ICD9: 303-304; ICD10: F10-F19]
Fragile X syndrome [ICD9: 332, 759.83; ICD10: F02.3, G20, Q99.2]
Nicotine dependence [ICD9: 305.1; ICD10: F17]
Partial seizures [ICD9: 345.4, 345.5; ICD10: G40.0, G40.2]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Schizophrenia [ICD9: 295; ICD10: F20]
Function
Component of a heterodimeric G-protein coupledreceptor 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 adenylatecyclase, 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.
BioChemical Class
GPCR glutamate
Target Validation
T42446
UniProt ID
O75899
Sequence
MASPRSSGQPGPPPPPPPPPARLLLLLLLPLLLPLAPGAWGWARGAPRPPPSSPPLSIMG
LMPLTKEVAKGSIGRGVLPAVELAIEQIRNESLLRPYFLDLRLYDTECDNAKGLKAFYDA
IKYGPNHLMVFGGVCPSVTSIIAESLQGWNLVQLSFAATTPVLADKKKYPYFFRTVPSDN
AVNPAILKLLKHYQWKRVGTLTQDVQRFSEVRNDLTGVLYGEDIEISDTESFSNDPCTSV
KKLKGNDVRIILGQFDQNMAAKVFCCAYEENMYGSKYQWIIPGWYEPSWWEQVHTEANSS
RCLRKNLLAAMEGYIGVDFEPLSSKQIKTISGKTPQQYEREYNNKRSGVGPSKFHGYAYD
GIWVIAKTLQRAMETLHASSRHQRIQDFNYTDHTLGRIILNAMNETNFFGVTGQVVFRNG
ERMGTIKFTQFQDSREVKVGEYNAVADTLEIINDTIRFQGSEPPKDKTIILEQLRKISLP
LYSILSALTILGMIMASAFLFFNIKNRNQKLIKMSSPYMNNLIILGGMLSYASIFLFGLD
GSFVSEKTFETLCTVRTWILTVGYTTAFGAMFAKTWRVHAIFKNVKMKKKIIKDQKLLVI
VGGMLLIDLCILICWQAVDPLRRTVEKYSMEPDPAGRDISIRPLLEHCENTHMTIWLGIV
YAYKGLLMLFGCFLAWETRNVSIPALNDSKYIGMSVYNVGIMCIIGAAVSFLTRDQPNVQ
FCIVALVIIFCSTITLCLVFVPKLITLRTNPDAATQNRRFQFTQNQKKEDSKTSTSVTSV
NQASTSRLEGLQSENHRLRMKITELDKDLEEVTMQLQDTPEKTTYIKQNHYQELNDILNL
GNFTESTDGGKAILKNHLDQNPQLQWNTTEPSRTCKDPIEDINSPEHIQRRLSLQLPILH
HAYLPSIGGVDASCVSPCVSPTASPRHRHVPPSFRVMVSGL
Structure
4F11; 4F12; 4MQE; 4MQF; 4MR7; 4MR8; 4MR9; 4MRM; 4MS1; 4MS3; 4MS4; 4PAS; 4MQE; 4MQF; 4MR7; 4MR8; 4MR9; 4MRM; 4MS1; 4MS3; 4MS4; 4PAS
Drugs and Mode of Action
Drug(s) Gabapentin Drug Info Approved Partial seizures [1], [2]
Progabide Drug Info Approved Depression [3]
Gabapentin Drug Info Phase 3 Cancer [2], [4]
STX209 Drug Info Phase 3 Fragile X syndrome [5]
SGS742 Drug Info Phase 2 Schizophrenia [6]
SCH 50911 Drug Info Terminated Absence seizures [7], [8]
Inhibitor ((E)-3-Amino-propenyl)-methyl-phosphinic acid Drug Info [9]
((Z)-3-Amino-propenyl)-methyl-phosphinic acid Drug Info [9]
(3-Amino-1-ethyl-propyl)-methyl-phosphinic acid Drug Info [9]
(3-Amino-1-hydroxy-propyl)-methyl-phosphinic acid Drug Info [9]
(3-Amino-phenyl)-phosphonic acid diphenyl ester Drug Info [10]
(3-Amino-propyl)-difluoromethyl-phosphinic acid Drug Info [9]
(3-Amino-propyl)-hexyl-phosphinic acid Drug Info [11]
(3-Amino-propyl)-hydroxymethyl-phosphinic acid Drug Info [9]
(3-Amino-propyl)-phosphonic acid Drug Info [10]
(R)-4-Amino-3-(4-chloro-phenyl)-butyric acid Drug Info [12]
(R)-5-Amino-3-(4-chloro-phenyl)-pentanoic acid Drug Info [12]
3-Amino-propane-1-sulfonic acid Drug Info [11]
3-ammoniopropane-1-sulfinate Drug Info [13]
4-Amino-3-(2-chloro-phenyl)-butyric acid Drug Info [14]
4-Amino-3-(4-fluoro-phenyl)-butyric acid Drug Info [14]
4-Amino-3-(5-bromo-thiophen-2-yl)-butyric acid Drug Info [14]
4-Amino-3-(5-chloro-thiophen-2-yl)-butyric acid Drug Info [14]
4-Amino-3-(5-methyl-thiophen-2-yl)-butyric acid Drug Info [14]
4-Amino-3-benzofuran-2-yl-butyric acid Drug Info [15]
4-Amino-3-thiophen-2-yl-butyric acid Drug Info [14]
CGP-27492 Drug Info [11]
CGP-34938 Drug Info [9]
CGP-35024 Drug Info [11]
CGP-35582 Drug Info [9]
CGP-36216 Drug Info [11]
GAMMA-AMINO-BUTANOIC ACID Drug Info [14]
Antagonist 2-hydroxy-saclofen Drug Info [16]
CGP 54626A Drug Info [16]
CGP 56999A Drug Info [16]
CGP 62349 Drug Info [16]
CGP 64213 Drug Info [16]
CGP 71872 Drug Info [16]
Gabapentin Drug Info [17]
Phaclofen Drug Info [18], [19]
saclofen Drug Info [16]
SCH 50911 Drug Info [20]
[125I]CGP 64213 Drug Info [16]
[125I]CGP 71872 Drug Info [16]
Agonist amino-propylphosphinic acid Drug Info [16]
CGP 47656 Drug Info [16]
CGP-44532 Drug Info [21], [22]
Progabide Drug Info [23], [24], [25]
SKF-97541 Drug Info [21]
TG-3030 Drug Info [26]
Modulator BHF-177 Drug Info [26]
CGP-29030A Drug Info [27], [4]
GABA-B receptor PAM Drug Info [26]
SGS742 Drug Info [6]
STX209 Drug Info [26]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway cAMP signaling pathway
Neuroactive ligand-receptor interaction
GABAergic synapse
Estrogen signaling pathway
Morphine addiction
Reactome Activation of G protein gated Potassium channels
G alpha (i) signalling events
Class C/3 (Metabotropic glutamate/pheromone receptors)
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits
WikiPathways GPCRs, Class C Metabotropic glutamate, pheromone
Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell
Potassium Channels
GPCR ligand binding
GPCR downstream signaling
References
REF 1Use of second-generation antiepileptic drugs in the pediatric population. Paediatr Drugs. 2008;10(4):217-54.
REF 2(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5483).
REF 3Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77. Epub 2007 Feb 20.
REF 4Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 5ClinicalTrials.gov (NCT01706523) Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders. U.S. National Institutes of Health.
REF 6SGS742: the first GABA(B) receptor antagonist in clinical trials. Biochem Pharmacol. 2004 Oct 15;68(8):1479-87.
REF 7(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 1075).
REF 8Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005684)
REF 9J Med Chem. 1995 Aug 18;38(17):3297-312.Phosphinic acid analogues of GABA. 1. New potent and selective GABAB agonists.
REF 10J Med Chem. 1984 May;27(5):654-9.Phosphorus analogues of gamma-aminobutyric acid, a new class of anticonvulsants.
REF 11Biological activity of 3-aminopropyl (methyl) phosphinic acid, a potent and selective GABAB agonist with CNS activity, Bioorg. Med. Chem. Lett. 3(4):515-518 (1993).
REF 12J Med Chem. 1999 Jun 3;42(11):2053-9.Synthesis and pharmacology of the baclofen homologues 5-amino-4-(4-chlorophenyl)pentanoic acid and the R- and S-enantiomers of 5-amino-3-(4-chlorophenyl)pentanoicacid.
REF 13A study of 3-amino-N-hydroxypropanesulfonamide derivatives as potential GABAB agonists and their fragmentation to 3-aminopropanesulfinic acid, Bioorg. Med. Chem. Lett. 6(14):1709-1714 (1996).
REF 14J Med Chem. 1991 Aug;34(8):2557-60.3-Thienyl- and 3-furylaminobutyric acids. Synthesis and binding GABAB receptor studies.
REF 15J Med Chem. 1987 Apr;30(4):743-6.Synthesis and pharmacological evaluation of gamma-aminobutyric acid analogues. New ligand for GABAB sites.
REF 16Expression cloning of GABA(B) receptors uncovers similarity to metabotropic glutamate receptors. Nature. 1997 Mar 20;386(6622):239-46.
REF 17Gabapentin increases a tonic inhibitory conductance in hippocampal pyramidal neurons. Anesthesiology. 2006 Aug;105(2):325-33.
REF 18The role of group II and III metabotropic glutamate receptors in modulation of miniature synaptic activity in frog spinal cord motoneurons. Tsitologiia. 2008;50(9):747-56.
REF 19Astrocytes and Interneurons in Memory Processing in the Chick Hippocampus: Roles for G-Coupled Protein Receptors, GABA(B) and mGluR1. Neurochem Res. 2009 May 5.
REF 20Activation of nigral dopamine neurons by the selective GABA(B)-receptor antagonist SCH 50911. J Neural Transm. 1999;106(5-6):383-94.
REF 21Inhibition of transient LES relaxations and reflux in ferrets by GABA receptor agonists. Am J Physiol. 1999 Oct;277(4 Pt 1):G867-74.
REF 22Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17.
REF 23Suppression by progabide of ethanol withdrawal syndrome in rats. Eur J Pharmacol. 1985 Mar 12;109(3):321-5.
REF 24Pentobarbital-like discriminative stimulus effects of direct GABA agonists in rats. Psychopharmacology (Berl). 1993;110(3):295-301.
REF 25Interactions between dopamine and GABA in the control of ambulatory activity and neophobia in the mouse. Pharmacol Biochem Behav. 1998 Jan;59(1):239-47.
REF 26(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 241).
REF 27Effects of a novel piperazine derivative (CGP 29030A) on nociceptive dorsal horn neurons in the rat. Drugs Exp Clin Res. 1992;18(11-12):447-59.

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