GABA<sub>B</sub> receptor | GABA<sub>B</sub> receptors | IUPHAR/BPS Guide to PHARMACOLOGY

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GABAB receptor

Target not currently curated in GtoImmuPdb

Target id: 242

Nomenclature: GABAB receptor

Family: GABAB receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

Quaternary Structure: Subunits
KCTD8 (Accessory protein)
KCTD12 (Accessory protein)
kctd12b (Accessory protein)
KCTD16 (Accessory protein)
GABAB1
GABAB2
Database Links
SynPHARM
Selected 3D Structures
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
GABA
Comments: Functional GABA receptors contain both GABAB1 and GABAB2 subunits

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
3-APPA Hs Full agonist 5.2 – 7.2 pKi 13
pKi 5.2 – 7.2 [13]
GABA Hs Full agonist 4.1 – 6.7 pKi 13,24
pKi 4.1 – 6.7 [13,24]
baclofen Hs Full agonist 4.3 – 6.2 pKi 13,24
pKi 4.3 – 6.2 [13,24]
3-APMPA Hs Full agonist 5.1 pKi 24
pKi 5.1 [24]
3-APPA Rn Agonist 9.7 pIC50 7
pIC50 9.7 [7]
CGP 44532 Rn Full agonist 8.6 pIC50 7
pIC50 8.6 [7]
(-)-baclofen Rn Full agonist 8.5 pIC50 7
pIC50 8.5 [7]
GABA Rn Full agonist 8.3 pIC50 7
pIC50 8.3 [7]
3-APMPA Rn Full agonist 8.2 pIC50 7
pIC50 8.2 [7]
[3H](R)-(-)-baclofen 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 Rn Antagonist 9.1 pKd 16
pKd 9.1 (Kd 9x10-10 M) [16]
[125I]CGP 64213 Rn Antagonist 9.0 pKd 8
pKd 9.0 (Kd 1x10-9 M) [8]
[125I]CGP 71872 Rn Antagonist 9.0 pKd 15
pKd 9.0 (Kd 1x10-9 M) [15]
[3H]CGP 54626 Rn Antagonist 9.1 pKi 14
pKi 9.1 (Ki 7.9x10-10 M) [14]
CGP 62349 Hs Antagonist 8.5 – 8.9 pKi 13,24
pKi 8.5 – 8.9 [13,24]
CGP 54626A Hs Antagonist 8.1 – 8.2 pKi 13,24
pKi 8.1 – 8.2 [13,24]
CGP 55845 Hs Antagonist 7.8 pKi 24
pKi 7.8 [24]
SCH 50911 Hs Antagonist 5.5 – 6.0 pKi 13,24
pKi 5.5 – 6.0 [13,24]
CGP 46381 Hs Antagonist 5.3 pKi 24
pKi 5.3 [24]
CGP 35348 Hs Antagonist 4.4 pKi 24
pKi 4.4 [24]
saclofen Hs Antagonist 3.7 – 4.3 pKi 13,24
pKi 3.7 – 4.3 [13,24]
phaclofen Hs Antagonist 3.9 pKi 24
pKi 3.9 [24]
CGP 55845 Rn Antagonist 9.8 pIC50 3
pIC50 9.8 [3]
SCH 50911 Rn Antagonist 6.5 pIC50 1
pIC50 6.5 [1]
CGP 36742 Rn Antagonist 5.6 pIC50 3
pIC50 5.6 [3]
CGP 35348 Rn Antagonist 5.4 pIC50 3
pIC50 5.4 [3]
saclofen Rn Antagonist 5.4 pIC50 3
pIC50 5.4 [3]
2-hydroxy-saclofen Rn Antagonist 4.1 pIC50 15
pIC50 4.1 [15]
phaclofen 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 Hs Positive 4.7 pKB 11,22
pKB 4.7 [11,22]
rac-BHFF Hs Positive 6.6 pEC50 18
pEC50 6.6 (EC50 2.34x10-7 M) [18]
compound 14 [PMID: 25050158] Hs Negative 4.4 pIC50 4
pIC50 4.4 (IC50 3.79x10-5 M) [4]
Description: Negative modulation of GABA-induced IP3 production.
CGP7930 Hs Positive - - 21
[21]
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Potassium channel
References:  14,17,25
Secondary Transduction Mechanisms
Transducer Effector/Response
Adenylate 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
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
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
Modulation of nociceptive transmission in the spinal cord to inhibit neuropathic hyperalgesia.
Species:  Rat
Tissue:  In vivo.
References:  20
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 receptorantagonist. J Pharmacol Exp Ther., 274: 1393-1398. [PMID:7562513]

2. Bonanno G, Raiteri M. (1993) gamma-Aminobutyric acid (GABA) autoreceptors in rat cerebral cortex and spinalcord represent pharmacologically distinct subtypes of the GABAB receptor. J Pharmacol Exp Ther., 265: 765-770. [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-aminobutyricacid(B) receptors: structure and function. Pharmacol Rev., 54: 247-264. [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 thalamocorticalcells. Trends Neurosci., 14: 16-21. [PMID:1709527]

6. Dutar P, Nicoll RA. (1988) A physiological role for GABAB receptors in the central nervous system. Nature, 332: 156-158. [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: 558-562. [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: 249-257. [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: 1103-1113. [PMID:12663046]

14. Jones KA, Borowsky B, Tamm JA, Craig DA, Durkin MM, Dai M, Yao WJ, Johnson M, Gunwaldsen C, Huang LY, Tang C, Shen Q, Salon JA, Morse K, Laz T, Smith KE, Nagarathnam D, Noble SA, Branchek TA, Gerald C. (1998) GABAB receptors function as a heteromeric assembly of the subunits GABABR1 and GABABR2. Nature, 396: 674-679. [PMID:9872315]

15. Kaupmann K, Huggel K, Heid J, Flor PJ, Bischoff S, Mickel SJ, McMaster G, Angst C, Bittiger H, Froestl W, Bettler B. (1997) Expression cloning of GABAB receptors uncovers similarity to metabotropic glutamate receptors. Nature, 386: 239-246. [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: 703-712. [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: 450-452. [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: 217-226. [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-aminobutyricacid(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: 963-971. [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 ofgamma-aminobutyric acidB receptor function. J Pharmacol Exp Ther., 307: 322-330. [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: 461-472. [PMID:11166132]

24. Wood MD, Murkitt KL, Rice SQ, Testa T, Punia PK, Stammers M, Jenkins O, Elshourbagy NA, Shabon U, Taylor SJ, Gager TL, Minton J, Hirst WD, Price GW, Pangalos M. (2000) The human GABA(B1b) and GABA(B2) heterodimeric recombinant receptor shows low sensitivity to phaclofen and saclofen. Br J Pharmacol, 131: 1050-1054. [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: 568-573. [PMID:2430096]

Contributors

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How to cite this page

Bernhard Bettler, Norman G. Bowery, John F. Cryan, Sam J. Enna, David H. Farb, Wolfgang Foestl, Klemens Kaupmann, Jean-Philippe Pin.
GABAB receptors: GABAB receptor. Last modified on 04/03/2019. Accessed on 25/06/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=242.