GABAB receptors

Overview

Functional GABA_B receptors are formed from the heterodimerization of two similar 7TM subunits termed GABA_B1 and GABA_B2 [1,2,3,4,5]. GABA_B receptors are widespread in the CNS and regulate both... [read more] pre- and postsynaptic activity. The GABA_B1 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 GABA_B1 and GABA_B2 subunits allows transport of GABA_B1 to the cell surface and generates a functional receptor that can couple to signal transduction pathways such as high-voltage-activated Ca²⁺ channels (Ca_v2.1, Ca_v2.2), or inwardly rectifying potassium channels (Kir3) [6,1,7]. The GABA_B1 subunit harbours the GABA (orthosteric)-binding site within an extracellular domain (ECD) venus flytrap module (VTM), whereas the GABA_B2 subunit mediates G protein-coupled signalling [1,2,8,9]. The cryo-electron microscopy structures of the human full-length GABA_B1-GABA_B2 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 GABA_B 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 GABA_B2 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 GABA_B receptors is further increased through association with trafficking and effector proteins [17] and reviewed by [18]. The predominant GABA_B1a and GABA_B1b 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. GABA_B1a-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 GABA_B1b-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 GABA_B1a isoform to regulate axonal trafficking of GABA_B receptors and release of neurotransmitters [21].

References

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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.
11. Pin JP, Comps-Agrar L, Maurel D, et al. G-protein-coupled receptor oligomers: two or more for what? Lessons from mGlu and GABAB receptors. J Physiol (Lond.) 2009;587:5337-44.
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.
16. Pinard A, Seddik R, Bettler B. GABAB receptors: physiological functions and mechanisms of diversity. Adv Pharmacol 2010;58:231-55.
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 GABA_BR1a ligand to modulate synaptic transmission. Science 2019;363:.

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