GABAB receptors

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).

Overview

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Functional GABAB receptors (nomenclature agreed by NC-IUPHAR Subcommittee on GABAB receptors, [6,30]) are formed from the heterodimerization of two similar 7TM subunits termed GABAB1 and GABAB2 [6,10,29-30,37]. GABAB receptors are widespread in the CNS and regulate both pre- and post-synaptic 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. The GABAB1 subunit when expressed alone is not transported to the cell membrane and is non-functional. 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 GABAB2 subunit also determines the rate of internalisation of the dimeric GABAB receptor [17]. 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 [6,16,29]. The two subunits interact by direct allosteric coupling [27], such that GABAB2 increases the affinity of GABAB1 for agonists and reciprocally GABAB1 facilitates the coupling of GABAB2 to G proteins [23,29]. GABAB1 and GABAB2 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 GABAB1 subunit but other domains of the proteins also contribute to their heteromerization [4,29]. 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 [8,28]. 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 [2,34] and reviewed by [31]. Four isoforms of the human GABAB1 subunit have been cloned. The predominant GABAB1(a) and GABAB1(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. GABAB1(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 GABAB1(b)-containing receptors occur within dendritic spines and mediate slow postsynaptic inhibition [32,39]. Isoforms generated by alternative splicing are GABAB1(c) that differs in the ECD, and GABAB1(e), which is a truncated protein that can heterodimerize with the GABAB2 subunit but does not constitute a functional receptor. Only the 1a and 1b variants are identified as components of native receptors [6]. Additional GABAB1 subunit isoforms have been described in rodents and humans [24] and reviewed by [4].

Receptors

GABAB receptor Show summary » More detailed page

Subunits

GABAB1 Show summary » More detailed page

GABAB2 Show summary » More detailed page

Accessory proteins

KCTD8 Show summary » More detailed page

KCTD12 Show summary » More detailed page

kcdt12b Show summary » More detailed page

KCTD16 Show summary » More detailed page

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NC-IUPHAR subcommittee and family contributors

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How to cite this family page

Database page citation:

GABAB receptors. Accessed on 24/04/2014. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=26.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, Peters JA and Harmar AJ, CGTP Collaborators. (2013) The Concise Guide to PHARMACOLOGY 2013/14: G Protein-Coupled Receptors. Br J Pharmacol. 170: 1459–1581.