Functional GABA_B receptors (nomenclature agreed by NC-IUPHAR Subcommittee on GABA_B receptors, [6,29]) are formed from the heterodimerization of two similar 7TM subunits termed GABA_B1 and GABA_B2 [6,10,28-29,36]. GABA_B receptors are widespread in the CNS and regulate both pre- and post-synaptic 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. The GABA_B1 subunit when expressed alone is not transported to the cell membrane and is non-functional. 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) [4,6-7]. The GABA_B2 subunit also determines the rate of internalisation of the dimeric GABA_B receptor [16]. 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 [6,28]. The two subunits interact by direct allosteric coupling [26], such that GABA_B2 increases the affinity of GABA_B1 for agonists and reciprocally GABA_B1 facilitates the coupling of GABA_B2 to G proteins [22,28]. GABA_B1 and GABA_B2 subunits assemble in a 1:1 stoichiometry by means of a coiled-coil interaction between α-helices within their carboxy-termini that masks an endoplasmic reticulum retention motif (RXRR) within the GABA_B1 subunit but other domains of the proteins also contribute to their heteromerization [4,28]. 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 [8,27]. 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 [2,33] and reviewed by [30]. Four isoforms of the human GABA_B1 subunit have been cloned. The predominant GABA_B1(a) and GABA_B1(b) 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_B1(a)-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_B1(b)-containing receptors occur within dendritic spines and mediate slow postsynaptic inhibition [31,38]. Isoforms generated by alternative splicing are GABA_B1(c) that differs in the ECD, and GABA_B1(e), which is a truncated protein that can heterodimerize with the GABA_B2 subunit but does not constitute a functional receptor. Only the 1a and 1b variants are identified as components of native receptors [6]. Additional GABA_B1 subunit isoforms have been described in rodents and humans [23] and reviewed by [4].

Potencies of agonists and antagonists listed in the table, quantified as IC₅₀ values for the inhibition of [³H]CGP27492 binding to rat cerebral cortex membranes, are from [6,12-13]. Radioligand K_D values relate to binding to rat brain membranes. CGP 71872 is a photoaffinity ligand for the GABA_B1 subunit [3]. CGP27492 (3-APPA), CGP35024 (3-APMPA) and CGP 44532 act as antagonists at human GABA_A ρ1 receptors, with potencies in the low micromolar range [12]. In addition to the ligands listed in the table, Ca²⁺ binds to the VTM of the GABA_B1 subunit to act as a positive allosteric modulator of GABA [14]. In cerebellar Purkinje neurones, the interaction of Ca²⁺ with the GABA_B receptor enhances the activity of mGlu₁, through functional cross-talk involving G-protein Gβγ subunits [32,35]. Synthetic positive allosteric modulators with low, or no, intrinsic activity include CGP7930, GS39783, BHF-177 and (+)-BHFF [1,4-5,12]. The site of action of CGP7930 and GS39783 appears to be on the heptahelical domain of the GABA_B2 subunit [9,28]. In the presence of CGP7930, or GS39783, CGP 35348 and 2-hydroxy-saclofen behave as partial agonists [12]. Knock-out of the GABA_B1 subunit in C57B mice causes the development of severe tonic-clonic convulsions that prove fatal within a month of birth, whereas GABA_B1^−/− BALB/c mice, although also displaying spontaneous epileptiform activity, are viable. The phenotype of the latter animals additionally includes hyperalgesia, hyperlocomotion (in a novel, but not familiar, environment), hyperdopaminergia, memory impairment and behaviours indicative of anxiety [11,37]. A similar phenotype has been found for GABA_B2^−/− BALB/c mice [15].

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