GABAB receptors: Introduction

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GABAB receptors are G protein-coupled receptors that are composed of principal GABAB1 and GABAB2 subunits, which form the core of the receptor, and auxiliary K-channel tetramerization domain (KCTD) subunits [8,12,14,19,22]. KCTD proteins bind as tetramers to the GABAB2 subunit and differentially modulate kinetic and pharmacological properties of the receptor response. The pharmacology is sufficiently homogeneous to allow the designation 'GABAB receptor' [10] to contrast with the ionotropic GABAA receptor [2].

The receptor was initially demonstrated on presynaptic terminals, where it acts as both an autoreceptor and a heteroreceptor to influence transmitter release by suppressing neuronal Ca2+ conductance. Subsequent studies, in particular in the rodent hippocampus [18], showed the presence of the receptor on postsynaptic neurones. Activation at this site produces neuronal hyperpolarization by increasing membrane K+ conductance. The antispastic agent, (-)-baclofen, is a highly selective agonist for GABAB receptors whilst the classical GABAA receptor antagonists, bicuculline and picrotoxin, fail to block GABAB receptors. The receptor is Gi/Go protein-coupled and thus, in addition to the association with membrane channels, it has mixed effects on adenylate cyclase activity [9,23].

Receptor nomenclature

The term GABAB receptor is sufficient to describe all the known pharmacology irrespective of the location of the receptor. Where recombinant receptors are studied, the variants should be indicated by lower-case letters and numerals for both subunits, e.g. GABAB1a,2a receptor, where 1 and 2 refer to the subunits, and a refers to the variants. At least eight variant forms (a-h) have so far been proposed for subunit 1, with the N-terminal 1a and 1b variants being the most prominent [11,13]. Originally subunit 2 was thought to have at least two splice variants but now genomic and RNA analysis supports a single form of subunit 2 [17]. The most abundant GABAB1 subunit isoforms, GABAB1a and GABAB1b, differ in in their N-terminal extracellular regions, where GABAB1a but not GABAB1b contains a pair of sushi domains. The sushi domains function as axonal trafficking signals and localize GABAB1a-containing receptors to glutamatergic terminals [1].

The term receptor only refers to the heterodimer. The component parts are referred to as subunits. Therefore naming the subunits R1 and R2 is discouraged and terms such as GBR1 should not be used. Thus mRNA for GB1a would now be mRNA GABAB(1a) and for GB2, mRNA GABAB(2). This nomenclature system allows for the possible discovery of further subunits, e.g. GABAB(3).

Evidence indicates that both the individual subunits are required to be co-expressed and coupled within the cell membrane to obtain a functional GABAB receptor [21]. Whilst individual splice variants of the subunits incorporated into the receptor may differ from region to region it appears that chimeric modifications in the subunits eliminates functionality. Thus, for example, substitution of one mGlu4 subunit for GABAB(2) fails to produce a functional receptor [15].

Receptor autoradiography of native GABAB receptors and immunohistochemistry of GABAB(1) and GABAB(2) proteins indicate comparable distributions in the mammalian brain [3-4,6,16,20]. mRNAs for GABAB(1) and GABAB(2) are also similarly distributed although in some brain regions, such as the caudate putamen, GABAB(1) mRNA is present whereas GABAB(2) mRNA appears to be absent [5]. In addition it has been noted that there is a low level of GABAB(2) mRNA relative to GABAB(1) mRNA in the hypothalamus [12]. This may mean that another subunit, so far unidentified, dimerizes with GABAB(1) or possibly the level of mRNA for GABAB(2) is very low and this determines the level of expression of GABAB(1) in its role as a trafficking protein.

Pharmacology

Relatively few agonists have emerged with selective activity for GABAB receptors and even fewer with greater efficacy or affinity for the receptor than (-)-baclofen. The most obvious examples are 2APPA, and its methyl homologue APMPA. Despite this paucity of agonists a variety of effects have been attributed to the action of GABAB receptor agonists and GABAB receptor-mediated synaptic events in mammals. These include centrally mediated muscle relaxation, antinociception, cognitive impairment, epileptogenesis, hypotension, reduced cocaine and heroin craving, brown fat thermogenesis, bronchiolar and urinary bladder relaxation, reduced release of corticotrophin releasing hormone, prolactin releasing hormone, luteinizing hormone and melanocyte stimulating hormone, yawning, and finally, antitussive and anti-hiccough actions.

The emergence of high affinity antagonists for GABAB receptors [7] has not only enabled their synaptic role to be established, but has also verified activation of the receptor in the pharmacological effects of GABA and (-)-baclofen. However, the antagonists discovered so far have generally failed to establish the existence of pharmacologically distinct receptor types within the GABAB receptor class.

References

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1. Biermann B, Ivankova-Susankova K, Bradaia A, Abdel Aziz S, Besseyrias V, Kapfhammer JP, Missler M, Gassmann M, Bettler B. (2010) The Sushi domains of GABAB receptors function as axonal targeting signals. J. Neurosci., 30 (4): 1385-94. [PMID:20107064]

2. Bowery NG. (1993) GABAB receptor pharmacology. Annu. Rev. Pharmacol. Toxicol., 33: 109-47. [PMID:8388192]

3. Bowery NG, Hudson AL, Price GW. (1987) GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience, 20 (2): 365-83. [PMID:3035421]

4. Chu DC, Albin RL, Young AB, Penney JB. (1990) Distribution and kinetics of GABAB binding sites in rat central nervous system: a quantitative autoradiographic study. Neuroscience, 34 (2): 341-57. [PMID:2159128]

5. Clark JA, Mezey E, Lam AS, Bonner TI. (1998) Functional expression and distribution of GB2 a second GABABreceptor. Soc. Neurosci. Abstr., 24: 795-798.

6. Fritschy JM, Meskenaite V, Weinmann O, Honer M, Benke D, Mohler H. (1999) GABAB-receptor splice variants GB1a and GB1b in rat brain: developmental regulation, cellular distribution and extrasynaptic localization. Eur. J. Neurosci., 11 (3): 761-8. [PMID:10103070]

7. Froestl W, Mickel SJ, von Sprecher G, Diel PJ, Hall RG, Maier L, Strub D, Melillo V, Baumann PA, Bernasconi R et al.. (1995) Phosphinic acid analogues of GABA. 2. Selective, orally active GABAB antagonists. J. Med. Chem., 38 (17): 3313-31. [PMID:7650685]

8. Gassmann M, Bettler B. (2012) Regulation of neuronal GABA(B) receptor functions by subunit composition. Nat. Rev. Neurosci., 13 (6): 380-94. [PMID:22595784]

9. Hill DR. (1985) GABAB receptor modulation of adenylate cyclase activity in rat brain slices. Br. J. Pharmacol., 84 (1): 249-57. [PMID:2579700]

10. Hill DR, Bowery NG. (1981) 3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABA B sites in rat brain. Nature, 290 (5802): 149-52. [PMID:6259535]

11. Isomoto S, Kaibara M, Sakurai-Yamashita Y, Nagayama Y, Uezono Y, Yano K, Taniyama K. (1998) Cloning and tissue distribution of novel splice variants of the rat GABAB receptor. Biochem. Biophys. Res. Commun., 253 (1): 10-5. [PMID:9875211]

12. Jones KA, Borowsky B, Tamm JA, Craig DA, Durkin MM, Dai M, Yao WJ, Johnson M, Gunwaldsen C, Huang LY et al.. (1998) GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2. Nature, 396 (6712): 674-9. [PMID:9872315]

13. Kaupmann K, Huggel K, Heid J, Flor PJ, Bischoff S, Mickel SJ, McMaster G, Angst C, Bittiger H, Froestl W et al.. (1997) Expression cloning of GABA(B) receptors uncovers similarity to metabotropic glutamate receptors. Nature, 386 (6622): 239-46. [PMID:9069281]

14. Kaupmann K, Malitschek B, Schuler V, Heid J, Froestl W, Beck P, Mosbacher J, Bischoff S, Kulik A, Shigemoto R et al.. (1998) GABA(B)-receptor subtypes assemble into functional heteromeric complexes. Nature, 396 (6712): 683-7. [PMID:9872317]

15. Margeta-Mitrovic M, Jan YN, Jan LY. (2000) A trafficking checkpoint controls GABA(B) receptor heterodimerization. Neuron, 27 (1): 97-106. [PMID:10939334]

16. Margeta-Mitrovic M, Mitrovic I, Riley RC, Jan LY, Basbaum AI. (1999) Immunohistochemical localization of GABA(B) receptors in the rat central nervous system. J. Comp. Neurol., 405 (3): 299-321. [PMID:10076927]

17. Martin SC, Russek SJ, Farb DH. (2001) Human GABA(B)R genomic structure: evidence for splice variants in GABA(B)R1 but not GABA(B)R2. Gene, 278: 63-79. [PMID:11707323]

18. Newberry NR, Nicoll RA. (1984) Direct hyperpolarizing action of baclofen on hippocampal pyramidal cells. Nature, 308 (5958): 450-2. [PMID:6709051]

19. Schwenk J, Metz M, Zolles G, Turecek R, Fritzius T, Bildl W, Tarusawa E, Kulik A, Unger A, Ivankova K et al.. (2010) Native GABA(B) receptors are heteromultimers with a family of auxiliary subunits. Nature, 465 (7295): 231-5. [PMID:20400944]

20. Sloviter RS, Ali-Akbarian L, Elliott RC, Bowery BJ, Bowery NG. (1999) Localization of GABAB(R1) receptors in the rat hippocampus by immunocytochemistry and high resolution autoradiography, with specific reference to its localization in identified hippocampal interneuron subpopulations. Neuropharmacology, 38: 1707-1721. [PMID:10587087]

21. Sullivan R, Chateauneuf A, Coulombe N, Kolakowski Jr LF, Johnson MP, Hebert TE, Ethier N, Belley M, Metters K, Abramovitz M et al.. (2000) Coexpression of full-length gamma-aminobutyric acid(B) (GABA(B)) receptors with truncated receptors and metabotropic glutamate receptor 4 supports the GABA(B) heterodimer as the functional receptor. J. Pharmacol. Exp. Ther., 293 (2): 460-7. [PMID:10773016]

22. White JH, Wise A, Main MJ, Green A, Fraser NJ, Disney GH, Barnes AA, Emson P, Foord SM, Marshall FH. (1998) Heterodimerization is required for the formation of a functional GABA(B) receptor. Nature, 396 (6712): 679-82. [PMID:9872316]

23. Xu J, Wojcik WJ. (1986) Gamma aminobutyric acid B receptor-mediated inhibition of adenylate cyclase in cultured cerebellar granule cells: blockade by islet-activating protein. J. Pharmacol. Exp. Ther., 239 (2): 568-73. [PMID:2430096]

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