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GABAB receptor

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Target not currently curated in GtoImmuPdb

Target id: 242

Nomenclature: GABAB receptor

Family: GABAB receptors

Contents:

Quaternary Structure: Subunits
KCTD8 (Accessory protein)
KCTD12 (Accessory protein)
kctd12b (Accessory protein)
KCTD16 (Accessory protein)
GABAB1
GABAB2
Database Links Click here for help
SynPHARM 2816 (in complex with baclofen)
2817 (in complex with CGP 35348)
2820 (in complex with CGP 46381)
2821 (in complex with CGP 54626A)
2814 (in complex with GABA)
2828 (in complex with phaclofen)
2826 (in complex with SCH 50911)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the extracellular domain of human GABA(B) receptor in the apo form
PDB Id:  4MQE
Resolution:  2.35Å
Species:  Human
References:  10
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the extracellular domain of human GABA(B) receptor bound to the antagonist 2-hydroxysaclofen
PDB Id:  4MQF
Ligand:  2-hydroxy-saclofen
Resolution:  2.22Å
Species:  Human
References:  10
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the extracellular domain of human GABA(B) receptor bound to the antagonist CGP54626
PDB Id:  4MR7
Ligand:  CGP 54626A
Resolution:  2.15Å
Species:  Human
References:  10
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the extracellular domain of human GABA(B) receptor bound to the antagonist SCH50911
PDB Id:  4MR9
Ligand:  SCH 50911
Resolution:  2.35Å
Species:  Human
References:  10
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the extracellular domain of human GABA(B) receptor bound to the antagonist CGP35348
PDB Id:  4MR8
Ligand:  CGP 35348
Resolution:  2.15Å
Species:  Human
References:  10
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the extracellular domain of human GABA(B) receptor bound to the antagonist phaclofen
PDB Id:  4MRM
Ligand:  phaclofen
Resolution:  2.86Å
Species:  Human
References:  10
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the extracellular domain of human GABA(B) receptor bound to the antagonist CGP46381
PDB Id:  4MS1
Ligand:  CGP 46381
Resolution:  2.25Å
Species:  Human
References:  10
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the extracellular domain of human GABA(B) receptor bound to the endogenous agonist GABA
PDB Id:  4MS3
Ligand:  GABA
Resolution:  2.5Å
Species:  Human
References:  10
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the extracellular domain of human GABA(B) receptor bound to the agonist baclofen
PDB Id:  4MS4
Ligand:  baclofen
Resolution:  1.9Å
Species:  Human
References:  10
Natural/Endogenous Ligands Click here for help
GABA
Comments: Functional GABA receptors contain both GABAB1 and GABAB2 subunits

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
3-APPA Small molecule or natural product Hs Full agonist 5.2 – 7.2 pKi 13
⤷ pKi 5.2 – 7.2 [13]
GABA Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 4.1 – 6.7 pKi 13,24
⤷ pKi 4.1 – 6.7 [13,24]
baclofen Small molecule or natural product Approved drug Primary target of this compound Hs Full agonist 4.3 – 6.2 pKi 13,24
⤷ pKi 4.3 – 6.2 [13,24]
3-APMPA Small molecule or natural product Ligand has a PDB structure Hs Full agonist 5.1 pKi 24
⤷ pKi 5.1 [24]
3-APPA Small molecule or natural product Click here for species-specific activity table Rn Agonist 9.7 pIC50 7
⤷ pIC50 9.7 [7]
CGP 44532 Small molecule or natural product Rn Full agonist 8.6 pIC50 7
⤷ pIC50 8.6 [7]
(-)-baclofen Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Rn Full agonist 8.5 pIC50 7
⤷ pIC50 8.5 [7]
GABA Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Rn Full agonist 8.3 pIC50 7
⤷ pIC50 8.3 [7]
3-APMPA Small molecule or natural product Ligand has a PDB structure Rn Full agonist 8.2 pIC50 7
⤷ pIC50 8.2 [7]
[3H](R)-(-)-baclofen Small molecule or natural product Ligand is labelled Ligand is radioactive Ligand has a PDB structure N/A Agonist - -
⤷
View species-specific agonist tables
Agonist Comments
Values included are those determined on the native receptor in which GABAB1 is associated with GABAB2. Affinity for agonists are at least 10 time lower when measured on GABAB1 alone.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]CGP 62349 Small molecule or natural product Ligand is labelled Ligand is radioactive Rn Antagonist 9.1 pKd 16
⤷ pKd 9.1 (Kd 9x10-10 M) [16]
[125I]CGP 64213 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Rn Antagonist 9.0 pKd 8
⤷ pKd 9.0 (Kd 1x10-9 M) [8]
[125I]CGP 71872 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Rn Antagonist 9.0 pKd 15
⤷ pKd 9.0 (Kd 1x10-9 M) [15]
[3H]CGP 54626 Small molecule or natural product Ligand is labelled Ligand is radioactive Ligand has a PDB structure Rn Antagonist 9.1 pKi 14
⤷ pKi 9.1 (Ki 7.9x10-10 M) [14]
CGP 62349 Small molecule or natural product Hs Antagonist 8.5 – 8.9 pKi 13,24
⤷ pKi 8.5 – 8.9 [13,24]
CGP 54626A Small molecule or natural product Ligand has a PDB structure Hs Antagonist 8.1 – 8.2 pKi 13,24
⤷ pKi 8.1 – 8.2 [13,24]
CGP 55845 Small molecule or natural product Ligand has a PDB structure Hs Antagonist 7.8 pKi 24
⤷ pKi 7.8 [24]
SCH 50911 Small molecule or natural product Ligand has a PDB structure Hs Antagonist 5.5 – 6.0 pKi 13,24
⤷ pKi 5.5 – 6.0 [13,24]
CGP 46381 Small molecule or natural product Ligand has a PDB structure Hs Antagonist 5.3 pKi 24
⤷ pKi 5.3 [24]
CGP 35348 Small molecule or natural product Ligand has a PDB structure Hs Antagonist 4.4 pKi 24
⤷ pKi 4.4 [24]
saclofen Small molecule or natural product Hs Antagonist 3.7 – 4.3 pKi 13,24
⤷ pKi 3.7 – 4.3 [13,24]
phaclofen Small molecule or natural product Hs Antagonist 3.9 pKi 24
⤷ pKi 3.9 [24]
CGP 55845 Small molecule or natural product Ligand has a PDB structure Rn Antagonist 9.8 pIC50 3
⤷ pIC50 9.8 [3]
SCH 50911 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Rn Antagonist 6.5 pIC50 1
⤷ pIC50 6.5 [1]
CGP 36742 Small molecule or natural product Rn Antagonist 5.6 pIC50 3
⤷ pIC50 5.6 [3]
CGP 35348 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Rn Antagonist 5.4 pIC50 3
⤷ pIC50 5.4 [3]
saclofen Small molecule or natural product Click here for species-specific activity table Rn Antagonist 5.4 pIC50 3
⤷ pIC50 5.4 [3]
2-hydroxy-saclofen Small molecule or natural product Click here for species-specific activity table Rn Antagonist 4.1 pIC50 15
⤷ pIC50 4.1 [15]
phaclofen Small molecule or natural product Rn Antagonist 4.1 pIC50 3
⤷ pIC50 4.1 [3]
View species-specific antagonist tables
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
GS39783 Small molecule or natural product Ligand has a PDB structure Hs Positive 4.7 pKB 11,22
⤷ pKB 4.7 [11,22]
rac-BHFF Small molecule or natural product Hs Positive 6.6 pEC50 18
⤷ pEC50 6.6 (EC50 2.34x10-7 M) [18]
compound 14 [PMID: 25050158] Small molecule or natural product Hs Negative 4.4 pIC50 4
⤷ pIC50 4.4 (IC50 3.79x10-5 M) [4]
Description: Negative modulation of GABA-induced IP3 production.
CGP7930 Small molecule or natural product Hs Positive - - 21
⤷ [21]
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Adenylyl cyclase inhibition
Potassium channel
References:  14,17,25
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Adenylyl cyclase stimulation
Comments:  Potentiation rather than stimulation. The GABAB1 subunit has been reported to interact with the transcription factor ATFx, and as such this receptor subunit has been proposed to generate signals that may be independent to G-protein. This however, requires further examination to be firmly established.
References:  12
Functional Assays Click here for help
Measurement of cAMP accumulation.
Species:  Rat
Tissue:  Cerebral cortex slices.
Response measured:  Inhibition of cAMP accumulation.
References:  12,25
Measurements of the membrane potential of hippocampal cells.
Species:  Human
Tissue:  Hippocampal slice.
Response measured:  Neuronal membrane hyperpolarisation.
References:  19
Measurement of K+ current in Xenopus oocytes transfected with both GABAB1 and GABAB2 as well as GIRK subunits.
Species:  Rat
Tissue:  Xenopus oocytes.
Response measured:  Production of K+ currents.
References:  14
Measurement of K+ current in HEK 293 cells transfected with both GABAB1 and GABAB2 as well as GIRK subunits.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Production of K+ currents.
References:  14
Measurement of intracellular Ca2+ increase using a Fluorometric Imaging Plate Reader (FLIPR) in CHO cells transfected with human GABAB1 and GABAB2.
Species:  Human
Tissue:  CHO cells.
Response measured:  Increase intracellular Ca2+ levels.
References:  24
Measurement of cAMP accumulation in CHO cells trasfected with both GABAB1 and GABAB2 subunits.
Species:  Human
Tissue:  CHO cells.
Response measured:  Inhibition of cAMP acuumulation.
References:  13
Physiological Functions Click here for help
Modulation of nociceptive transmission in the spinal cord to inhibit neuropathic hyperalgesia.
Species:  Rat
Tissue:  In vivo.
References:  20
Reduction in evoked release of neurotransmitter.
Species:  Rat
Tissue:  Brain and spinal cord slices.
References:  2
Synaptic hyperpolarization, late phase.
Species:  Rat
Tissue:  Hippocampal and thalamic slices.
References:  5-6
Inhibition of somatostatin and cholecystokinin release.
Species:  Rat
Tissue:  Cerebrocortical synaptosomes.
References:  9
Direct modulation of Ca2+ channels. May be the mechanism by which receptor agonists cause antinociception.
Species:  Rat
Tissue:  Spinal cord.
References:  23

References

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1. Bolser DC, Blythin DJ, Chapman RW, Egan RW, Hey JA, Rizzo C, Kuo SC, Kreutner W. (1995) The pharmacology of SCH 50911: a novel, orally-active GABA-beta receptor antagonist. J Pharmacol Exp Ther, 274 (3): 1393-8. [PMID:7562513]

2. Bonanno G, Raiteri M. (1993) gamma-Aminobutyric acid (GABA) autoreceptors in rat cerebral cortex and spinal cord represent pharmacologically distinct subtypes of the GABAB receptor. J Pharmacol Exp Ther, 265 (2): 765-70. [PMID:8388458]

3. Bowery NG, Bettler B, Froestl W, Gallagher JP, Marshall F, Raiteri M, Bonner TI, Enna SJ. (2002) International Union of Pharmacology. XXXIII. Mammalian gamma-aminobutyric acid(B) receptors: structure and function. Pharmacol Rev, 54 (2): 247-64. [PMID:12037141]

4. Chen LH, Sun B, Zhang Y, Xu TJ, Xia ZX, Liu JF, Nan FJ. (2014) Discovery of a Negative Allosteric Modulator of GABAB Receptors. ACS Med Chem Lett, 5 (7): 742-7. [PMID:25050158]

5. Crunelli V, Leresche N. (1991) A role for GABAB receptors in excitation and inhibition of thalamocortical cells. Trends Neurosci, 14 (1): 16-21. [PMID:1709527]

6. Dutar P, Nicoll RA. (1988) A physiological role for GABAB receptors in the central nervous system. Nature, 332 (6160): 156-8. [PMID:2831457]

7. Froestl W, Mickel SJ. (1997) Chemistry of GABAB modulators. In The GABA Receptors. Edited by Enna SJ, Bowery NG (Humana Press) 271-296. [ISBN:0896034585]

8. Galvez T, Urwyler S, Prézeau L, Mosbacher J, Joly C, Malitschek B, Heid J, Brabet I, Froestl W, Bettler B et al.. (2000) Ca(2+) requirement for high-affinity gamma-aminobutyric acid (GABA) binding at GABA(B) receptors: involvement of serine 269 of the GABA(B)R1 subunit. Mol Pharmacol, 57 (3): 419-26. [PMID:10692480]

9. Gemignani A, Paudice P, Bonanno G, Raiteri M. (1994) Pharmacological discrimination between gamma-aminobutyric acid type B receptors regulating cholecystokinin and somatostatin release from rat neocortex synaptosomes. Mol Pharmacol, 46 (3): 558-62. [PMID:7935338]

10. Geng Y, Bush M, Mosyak L, Wang F, Fan QR. (2013) Structural mechanism of ligand activation in human GABA(B) receptor. Nature, 504 (7479): 254-9. [PMID:24305054]

11. Hellyer SD, Albold S, Wang T, Chen ANY, May LT, Leach K, Gregory KJ. (2018) "Selective" Class C G Protein-Coupled Receptor Modulators Are Neutral or Biased mGlu5 Allosteric Ligands. Mol Pharmacol, 93 (5): 504-514. [PMID:29514854]

12. Hill DR. (1985) GABAB receptor modulation of adenylate cyclase activity in rat brain slices. Br J Pharmacol, 84 (1): 249-57. [PMID:2579700]

13. Hirst WD, Babbs AJ, Green A, Minton JA, Shaw TE, Wise A, Rice SQ, Pangalos MN, Price GW. (2003) Pharmacological characterisation of a cell line expressing GABA B1b and GABA B2 receptor subunits. Biochem Pharmacol, 65 (7): 1103-13. [PMID:12663046]

14. Jones KA, Borowsky B, Tamm JA, Craig DA, Durkin MM, Dai M, Yao WJ, Johnson M, Gunwaldsen C, Huang LY et al.. (1998) GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2. Nature, 396 (6712): 674-9. [PMID:9872315]

15. Kaupmann K, Huggel K, Heid J, Flor PJ, Bischoff S, Mickel SJ, McMaster G, Angst C, Bittiger H, Froestl W et al.. (1997) Expression cloning of GABA(B) receptors uncovers similarity to metabotropic glutamate receptors. Nature, 386 (6622): 239-46. [PMID:9069281]

16. Keir MJ, Barakat MJ, Dev KK, Bittiger H, Bettler B, Henley JM. (1999) Characterisation and partial purification of the GABA(B) receptor from the rat cerebellum using the novel antagonist [3H]CGP 62349. Brain Res Mol Brain Res, 71 (2): 279-89. [PMID:10521582]

17. Knight AR, Bowery NG. (1996) The pharmacology of adenylyl cyclase modulation by GABAB receptors in rat brain slices. Neuropharmacology, 35 (6): 703-12. [PMID:8887979]

18. Malherbe P, Masciadri R, Norcross RD, Knoflach F, Kratzeisen C, Zenner MT, Kolb Y, Marcuz A, Huwyler J, Nakagawa T et al.. (2008) Characterization of (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one as a positive allosteric modulator of GABAB receptors. Br J Pharmacol, 154 (4): 797-811. [PMID:18536733]

19. Newberry NR, Nicoll RA. (1984) Direct hyperpolarizing action of baclofen on hippocampal pyramidal cells. Nature, 308 (5958): 450-2. [PMID:6709051]

20. Patel S, Naeem S, Kesingland A, Froestl W, Capogna M, Urban L, Fox A. (2001) The effects of GABA(B) agonists and gabapentin on mechanical hyperalgesia in models of neuropathic and inflammatory pain in the rat. Pain, 90 (3): 217-26. [PMID:11207393]

21. Urwyler S, Mosbacher J, Lingenhoehl K, Heid J, Hofstetter K, Froestl W, Bettler B, Kaupmann K. (2001) Positive allosteric modulation of native and recombinant gamma-aminobutyric acid(B) receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501. Mol Pharmacol, 60 (5): 963-71. [PMID:11641424]

22. Urwyler S, Pozza MF, Lingenhoehl K, Mosbacher J, Lampert C, Froestl W, Koller M, Kaupmann K. (2003) N,N'-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) and structurally related compounds: novel allosteric enhancers of gamma-aminobutyric acidB receptor function. J Pharmacol Exp Ther, 307 (1): 322-30. [PMID:12954816]

23. Voisin DL, Nagy F. (2001) Sustained L-type calcium currents in dissociated deep dorsal horn neurons of the rat: characteristics and modulation. Neuroscience, 102 (2): 461-72. [PMID:11166132]

24. Wood MD, Murkitt KL, Rice SQ, Testa T, Punia PK, Stammers M, Jenkins O, Elshourbagy NA, Shabon U, Taylor SJ et al.. (2000) The human GABA(B1b) and GABA(B2) heterodimeric recombinant receptor shows low sensitivity to phaclofen and saclofen. Br J Pharmacol, 131 (6): 1050-4. [PMID:11082110]

25. Xu J, Wojcik WJ. (1986) Gamma aminobutyric acid B receptor-mediated inhibition of adenylate cyclase in cultured cerebellar granule cells: blockade by islet-activating protein. J Pharmacol Exp Ther, 239 (2): 568-73. [PMID:2430096]

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