1. University of Basel, Switzerland
2. GlaxoSmithKline, Italy
3. University College Cork, Ireland
4. University of Kansas Medical Center, USA
5. Boston University, USA
6. Novartis Institutes for Biomedical Research, Switzerland
7. Université de Montpellier, France

Abstract

Functional GABA_B receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on GABA_B receptors [11, 71]) are formed from the heterodimerization of two similar 7TM subunits termed GABA_B1 and GABA_B2 [11, 70, 28, 71, 87]. GABA_B receptors are widespread in the CNS and regulate both 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) [12, 11, 5]. 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 [11, 70, 40, 39]. 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 [81]. 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 [69, 22]. 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 [86, 3, 79] and are reviewed by [72]. The molecular complexity of GABA_B receptors is further increased through association with trafficking and effector proteins [80] and reviewed by [68]. 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 [74, 91]. 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 [76].

Contents

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