Human GABBR2

Figure. Concentration-dependent activation of GABBR1+GABBR2 by baclofen

Reporter cells were transfected with either the expression plasmid for human GABBR1+GABBR2 or the mock plasmid and treated with various concentrations of baclofen. Data points shown are the mean ± SEM of an experiment (n = 3), and the curve is a fit to Hill equation with an EC50 of 9.4 µM.

gamma-aminobutyric acid type B receptor subunit 2
Available assay modes
Agonist, Inverse agonist, Antagonist, PAM, NAM
à la carte, Psychiatry, Neurology, Musculoskeletal, Human non-orphan GPCRs

GABAB receptors

Functional GABAB receptors are formed from the heterodimerization of two similar 7TM subunits termed GABAB1 and GABAB2 [1,2,3,4,5]. GABAB receptors are widespread in the CNS and regulate both pre- and postsynaptic activity. The GABAB1 subunit, when expressed alone, binds both antagonists and agonists, but the affinity of the latter is generally 10-100-fold less than for the native receptor. Co-expression of GABAB1 and GABAB2 subunits allows transport of GABAB1 to the cell surface and generates a functional receptor that can couple to signal transduction pathways such as high-voltage-activated Ca2+ channels (Cav2.1, Cav2.2), or inwardly rectifying potassium channels (Kir3) [6,1,7]. The GABAB1 subunit harbours the GABA (orthosteric)-binding site within an extracellular domain (ECD) venus flytrap module (VTM), whereas the GABAB2 subunit mediates G protein-coupled signalling [1,2,8,9]. The cryo-electron microscopy structures of the human full-length GABAB1-GABAB2 heterodimer have been solved in the inactive apo state, two intermediate agonist-bound forms and an active state in which the heterodimer is bound to an agonist and a positive allosteric modulator [10]. The positive allosteric modulator binds to the transmembrane dimerization interface and stabilizes the active state. Recent evidence indicates that higher order assemblies of GABAB receptor comprising dimers of heterodimers occur in recombinant expression systems and in vivo and that such complexes exhibit negative functional cooperativity between heterodimers [11,12]. Adding further complexity, KCTD (potassium channel tetramerization proteins) 8, 12, 12b and 16 associate as tetramers with the carboxy terminus of the GABAB2 subunit to impart altered signalling kinetics and agonist potency to the receptor complex [13,14,15] and are reviewed by [16]. The molecular complexity of GABAB receptors is further increased through association with trafficking and effector proteins [17] and reviewed by [18]. The predominant GABAB1a and GABAB1b isoforms, which are most prevalent in neonatal and adult brain tissue respectively, differ in their ECD sequences as a result of the use of alternative transcription initiation sites. GABAB1a-containing heterodimers localise to distal axons and mediate inhibition of glutamate release in the CA3-CA1 terminals, and GABA release onto the layer 5 pyramidal neurons, whereas GABAB1b-containing receptors occur within dendritic spines and mediate slow postsynaptic inhibition [19,20]. Amyloid precursor protein (APP) and soluble APP (sAPP) bind to the N- terminal sushi domain of the GABAB1a isoform to regulate axonal trafficking of GABAB receptors and release of neurotransmitters [21].


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  10. Shaye H, Ishchenko A, Lam JH, et al. Structural basis of the activation of a metabotropic GABA receptor. Nature 2020;584:298-303.
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  12. Comps-Agrar L, Kniazeff J, Nørskov-Lauritsen L, et al. The oligomeric state sets GABA(B) receptor signalling efficacy. EMBO J 2011;30:2336-49.
  13. Turecek R, Schwenk J, Fritzius T, et al. Auxiliary GABAB receptor subunits uncouple G protein βγ subunits from effector channels to induce desensitization. Neuron 2014;82:1032-44.
  14. Bartoi T, Rigbolt KT, Du D, et al. GABAB receptor constituents revealed by tandem affinity purification from transgenic mice. J Biol Chem 2010;285:20625-33.
  15. Schwenk J, Metz M, Zolles G, et al. Native GABA(B) receptors are heteromultimers with a family of auxiliary subunits. Nature 2010;465:231-5.
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  17. Schwenk J, Pérez-Garci E, Schneider A, et al. Modular composition and dynamics of native GABAB receptors identified by high-resolution proteomics. Nat Neurosci 2016;19:233-42.
  18. Pin JP, Bettler B. Organization and functions of mGlu and GABAB receptor complexes. Nature 2016;540:60-68.
  19. Pérez-Garci E, Gassmann M, Bettler B, et al. The GABAB1b isoform mediates long-lasting inhibition of dendritic Ca2+ spikes in layer 5 somatosensory pyramidal neurons. Neuron 2006;50:603-16.
  20. Vigot R, Barbieri S, Bräuner-Osborne H, et al. Differential compartmentalization and distinct functions of GABAB receptor variants. Neuron 2006;50:589-601.
  21. Rice HC, de Malmazet D, Schreurs A, et al. Secreted amyloid-β precursor protein functions as a GABABR1a ligand to modulate synaptic transmission. Science 2019;363:.
Excerpt from IUPHAR/BPS Guide to Pharmacology

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