GABA_B

Overview: Functional GABA_B receptors (nomenclature agreed by NC-IUPHAR Subcommittee on GABA_B receptors, Bowery et al., 2002; see also Pin et al., 2007) are formed from the heterodimerization of two similar 7TM subunits termed GABA_B1 and GABA_B2 (Bowery et al., 2002; Pin et al., 2004; Emson, 2007; Pin et al., 2007; Ulrich and Bettler, 2007). 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) (Bowery and Enna, 2000; Bowery et al., 2002; Bettler et al., 2004). 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 (Bowery et al., 2002; Pin et al., 2004). The two subunits interact allosterically in that GABA_B2 increases the affinity of GABA_B1 for agonists and reciprocally GABA_B1 facilitates the coupling of GABA_B2 to G proteins (Pin et al., 2004; Kubo and Tateyama, 2005). 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 (Bettler et al., 2004; Pin et al., 2004). 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 localize 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 (Pérez-Garci et al., 2006; Vigot et al., 2006). 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 (Bowery et al., 2002). Additional GABA_B1 subunit isoforms have been described in rodents (reviewed by Bettler et al., 2004).

Nomenclature	GABAB
Ensembl ID	GABAB1 ENSG00000168760; GABAB2 ENSG00000136928
Principal transduction	Gi/o
Selective agonists	3-APPA (CGP27492, 5 nM), 3-APMPA (CGP35024, 16 nM), (R)-(-)-baclofen (32 nM), CGP44532 (45 nM)
Selective antagonists	CGP62349 (2.0 nM), CGP55845 (6 nM), SCH50911 (3 µM), 2-hydroxy-s-(-)-saclofen (11 µM), CGP35348 (27 µM)
Probes (KD)	[3H](R)-(-)-baclofen, [3H]CGP54626 (1.5 nM, Bittiger et al., 1992), [3H]CGP62349 (0.9 nM, Kier et al., 1999), [125I]CGP64213 (1 nM, Galvez et al., 2000), [125I]CGP71872 (Ki= 0.5 nM, Belley et al., 1999)

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 Froestl and Mickel (1997) and Bowery et al. (2002). Radioligand K_D values relate to binding to rat brain membranes. CGP71872 is a photoaffinity ligand for the GABA_B1 subunit (Belley et al., 1999). In addition to the ligands listed in the table, Ca²⁺ binds to a site on the GABA_B1 subunit to act as a positive allosteric modulator of GABA (Galvez et al., 2000). In cerebellar Purkinje neurones, the interaction of Ca²⁺ with the GABA_B receptor enhances the activity of mGlu1, most probably via a direct association between the two receptors (Tabata et al., 2004). Synthetic positive allosteric modulators with little, or no, intrinsic activity include CGP7930 and GS39783 (reviewed by Bettler et al., 2004; Adams and Lawrence, 2007). Their site of action appears to be on the heptahelical domain of the GABA_B2 subunit (Pin et al., 2004; Dupuis et al., 2006). Knockout 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 (Enna and Bowery, 2004; Vacher et al., 2006). A similar phenotype has been found for GABA_B2^−/− BALB/c mice (Gassmann et al., 2004).

Glossary

Abbreviations:

3-APMPA (CGP35024)

3-amino-propyl-(P-methyl)-phosphinic acid

3-APPA (CGP27492)

3-amino-propyl-phosphinic acid

CGP7930

2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol

CGP35348

p-(3-aminopropyl)-P-diethoxymethylphosphinic acid

CGP44532

3-amino-2-hydroxypropylmethylphosphinic acid

CGP54626

[S-(R,R)]-[3-[[1-(3,4-dichlorophenyl)ethyl]amino]-2-hydroxypropyl](cyclohexylmethyl)phosphinic acid

CGP55845

3-[-1-(S)-(3,4-dichlorphenyl)-ethyl]amino-2(S)-hydroxypropyl-(P-benzyl)-phosphinic acid

CGP62349

[3-[1-R-[[3-(methoxyphenylmethyl)hydroxyphosphinyl]-2(5)-hydroxypropyl]amino]ethyl]-benzoic acid

CGP64213

[3-[-(R)-[[3-5N-[1-[2-[[3-iodo-4-hydroxyphenyl]ethyl]carboxamido]pentyl]hydroxyphosphinyl]-2(S)-hydroxy-propyl]amino]ethyl-benzoic acid

CGP71872

3-(1-(R)-(3-((5-(4-azido-2-hydroxy-5-iodobenzoylamino)pentyl)hydroxyphosphoryl)-2-(S)-hydroxypropylamino)ethyl)benzoic acid

GS39783

N,N′-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine

SCH90511

(+)-(2S)-5,5-dimethyl-2-morpholineacetic acid

Further Reading

Bettler B, Tiao JY (2006). Molecular diversity, trafficking and subcellular localization of GABA_B receptors. Pharmacol Ther110: 533–543.

Bettler B, Kaupmann K, Mosbacher J, Gassmann M (2004). Molecular structure and physiological functions of GABA_B receptors. Physiol Rev84: 835–367.

Bowery NG (2000). Pharmacology of GABA_B receptors. Handb Exp Pharmacol150: 311–328.

Bowery NG (2006). GABA_B receptor: a site of therapeutic benefit. Curr Opin Pharmacol6: 37–43.

Bowery NG, Enna SJ (2000). γ-Aminobutyric acid_B receptors: first of the functional metabotropic heterodimers. J Pharmacol Exp Ther292: 2–7.

Bowery NG, Bettler B, Froestl W, Gallagher JP, Marshall F, Raiteri M et al. (2002). International Union of Pharmacology XXXIII. Mammalian γ-aminobutyric acid_B receptors: structure and function. Pharmacol Rev54: 247–264.

Cryan JF, Kaupmann K. (2005). Don't worry ‘B’ happy!: a role for GABA_B receptors in anxiety and depression. Trends Pharmacol Sci26: 36–43.

Emson PC (2007). GABA_B receptors: structure and function. Prog Brain Res160: 43–57.

Enna SJ, Bowery NG (2004). GABA_B receptor alterations as indicators of physiological and pharmacological function. Biochem Pharmacol68: 1541–1548.

Froestl W, Mickel SW (1997). Chemistry of GABA_B modulators. In: Enna SJ, Bowery NG (eds). The GABA Receptors. Humana Press: Totowa, NJ, pp. 271–296.

Kornau HC (2006). GABA_B receptors and synaptic modulation. Cell Tissue Res326: 517–533.

Kubo Y, Tateyama M (2005). Towards a view of functioning dimeric metabotropic receptors. Curr Opin Neurobiol15: 289–295.

Lehmann A (2009). GABA_B receptors as drug targets to treat gastroesophageal reflux disease. Pharmacol Ther122: 239–245.

Marshall FH (2005). Is the GABA B heterodimer a good drug target? J Mol Neurosci26: 169–176.

Pin J-P, Kniazeff J, Binet V, Liu J, Maurel D, Galvez T et al. (2004). Activation mechanism of the heterodimeric GABA_B receptor. Biochem Pharmacol68: 1565–1572.

Pin J-P, Neubig R, Bouvier M, Devi L, Filizola M, Javitch JA et al. (2007). International Union of Basic and Clinical Pharmacology. LXVII. Recommendations for the recognition and nomenclature of G protein-coupled receptor heteromultimers. Pharmacol Rev59: 5–13.

Ulrich D, Bettler B (2007). GABA_B receptors: synaptic functions and mechanisms of diversity. Curr Opin Neurobiol17: 298–303.