GABA_B receptors are G protein-coupled receptors that are composed of principal GABA_B1 and GABA_B2 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 'GABA_B receptor' [10] to contrast with the ionotropic GABA_A 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 GABA_B receptors whilst the classical GABA_A receptor antagonists, bicuculline and picrotoxin, fail to block GABA_B receptors. The receptor is G_i/G_o 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 GABA_B 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. GABA_B1a,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 GABA_B1 subunit isoforms, GABA_B1a and GABA_B1b, differ in in their N-terminal extracellular regions, where GABA_B1a but not GABA_B1b contains a pair of sushi domains. The sushi domains function as axonal trafficking signals and localize GABA_B1a-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 GABA_B(1a) and for GB2, mRNA GABA_B(2). This nomenclature system allows for the possible discovery of further subunits, e.g. GABA_B(3).

Evidence indicates that both the individual subunits are required to be co-expressed and coupled within the cell membrane to obtain a functional GABA_B 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 GABA_B(2) fails to produce a functional receptor [15].

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

Pharmacology

Relatively few agonists have emerged with selective activity for GABA_B 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 GABA_B receptor agonists and GABA_B 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 GABA_B 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 GABA_B receptor class.

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