GABAB receptors C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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Functional GABAB receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on GABAB receptors [6,31]) are formed from the heterodimerization of two similar 7TM subunits termed GABAB1 and GABAB2 [6,11,30-31,40]. 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) [4,6-7]. 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 [6,17-18,30]. 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 [37]. 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 [9,29]. 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 [2,35,39] and are reviewed by [32]. The molecular complexity of GABAB receptors is further increased through association with trafficking and effector proteins [36] and reviewed by [28]. 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 [33,44]. 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 [34].
Receptors
Complexes
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GABAB receptor
C
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Receptors and Subunits
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GABAB1
C
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GABAB2
C
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Accessory Proteins
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KCTD12
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kctd12b
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KCTD16
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Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
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 [6,13-14]. Radioligand KD values relate to binding to rat brain membranes. CGP 71872 is a photoaffinity ligand for the GABAB1 subunit [3]. CGP27492 (3-APPA), CGP35024 (3-APMPA) and CGP 44532 act as antagonists at human GABAA ρ1 receptors, with potencies in the low micromolar range [13]. In addition to the ligands listed in the table, Ca2+ binds to the VTM of the GABAB1 subunit to act as a positive allosteric modulator of GABA [15]. Synthetic positive allosteric modulators with low, or no, intrinsic activity include CGP7930, GS39783, BHF-177 [45] and (+)-BHFF [1,4-5,13]. The site of action of CGP7930 and GS39783 appears to be on the heptahelical domain of the GABAB2 subunit [10,30]. In the presence of CGP7930 or GS39783, CGP 35348 and 2-hydroxy-saclofen behave as partial agonists [13]. A negative allosteric modulator of GABAB activity has been reported [8]. Knock-out of the GABAB1 subunit in C57B mice causes the development of severe tonic-clonic convulsions that prove fatal within a month of birth, whereas GABAB1−/− 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 [12,43]. A similar phenotype has been found for GABAB2−/− BALB/c mice [16].