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Review
. 2018;94(10):390-411.
doi: 10.2183/pjab.94.026.

Diversity of Structure and Function of GABA B Receptors: A Complexity of GABA B-mediated Signaling

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Free PMC article
Review

Diversity of Structure and Function of GABA B Receptors: A Complexity of GABA B-mediated Signaling

Miho Terunuma. Proc Jpn Acad Ser B Phys Biol Sci. .
Free PMC article

Abstract

γ-aminobutyric acid type B (GABAB) receptors are broadly expressed in the nervous system and play an important role in neuronal excitability. GABAB receptors are G protein-coupled receptors that mediate slow and prolonged inhibitory action, via activation of Gαi/o-type proteins. GABAB receptors mediate their inhibitory action through activating inwardly rectifying K+ channels, inactivating voltage-gated Ca2+ channels, and inhibiting adenylate cyclase. Functional GABAB receptors are obligate heterodimers formed by the co-assembly of R1 and R2 subunits. It is well established that GABAB receptors interact not only with G proteins and effectors but also with various proteins. This review summarizes the structure, subunit isoforms, and function of GABAB receptors, and discusses the complexity of GABAB receptors, including how receptors are localized in specific subcellular compartments, the mechanism regulating cell surface expression and mobility of the receptors, and the diversity of receptor signaling through receptor crosstalk and interacting proteins.

Keywords: G protein-coupled receptors; GABAB receptors; di-/oligomerization; interacting proteins; posttranslational modification; trafficking.

Figures

Figure 1.
Figure 1.
Structural organization of GABAB receptors and the primary GABAB receptor effectors. Functional GABAB receptors form heterodimers composed of R1 and R2 subunits. Both subunits are heptahelical membrane proteins that have seven-transmembrane (7TM) domains with a large extracellular N-terminal domain containing a Venus flytrap (VFT) domain and a large intracellular C-terminal tail containing a coiled-coil protein–protein interaction module. The R1 subunit is responsible for ligand binding in the VFT domain, whereas the VFT of R2 subunit fails to bind any known ligands. Instead, the heptahelical domain of the R2 subunit contains a binding site for allosteric modulators, which affect the affinity of ligand binding to the R1 subunit. The interaction between the R1 and R2 subunits takes place at their C-terminus through the coiled-coil domains. The R1 subunit exists in two main isoforms. R1a is distinguished from R1b by the presence of two sushi domains (SDs). An endoplasmic reticulum (ER) retention signal (RSRR) is present distal to the coiled-coil domain in the R1 subunit and prevents the ER exit of R1 unless it is masked by an R2 subunit. The binding of GABA results in the recruitment and activation of Gαi/o proteins via the R2 subunit. The activated Gαi/o subunits inhibit adenylyl cyclase, resulting in lowered cAMP levels, while Gβγ subunits activate GIRK channels at postsynaptic sites and inhibit CaV channels at presynaptic sites, leading to neuronal inhibition.
Figure 2.
Figure 2.
GABAB receptor interacting proteins. A number of proteins have been found to interact with the C-terminus of GABAB receptor subunits. Among the interacting proteins are leucine-zipper transcription factors ATF4/CREB2 and CHOP, scaffolding and adaptor proteins 14-3-3, GISP, NSF, and PDZ domain-containing scaffold proteins Shrm4 and Mupp1. It is proposed that these proteins regulate receptor dimerization, intracellular trafficking, and synaptic localization. The C-terminus of the R2 subunit associates with KCTD proteins, which regulate CaV channel activity and GABAB receptor trafficking. The C-terminus of the R1 subunit associates with the brain-specific RNA binding protein Marlin-1 to target the cytoskeleton and regulate receptor transportation. Neurotransmitter receptors such as GABAA receptor γ2 subunit, mGluRs, and GIRK channels are also GABAB receptor binding partners although only the γ2 subunit has been identified to directly associate with R1 subunits so far. The N-terminus of R1 subunits also interact with proteins such as extracellular matrix protein fibulin-2 and tenascin. The extracellular sushi domains of the R1 subunit interact with fibulin-2, whereas tenascin binds to the extracellular domains of R1 subunits, possibly via the second transmembrane domain. Other proteins such as Gi/o proteins and RGS proteins bind to the R2 subunit to induce GPCR signaling.
Figure 3.
Figure 3.
Phosphorylation of GABAB receptors and their functional modulation. Five phosphorylation sites have been identified so far: serine 867 (S867) and S917/923 on the R1 subunit, and S783 and S892 on the R2 subunit. Calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylates S867 on R1 subunit and promotes dynamin-dependent receptor endocytosis. 5′AMP-dependent protein kinase (AMPK) has been found to phosphorylate S917/923 on the R1 subunit and S783 on the R2 subunit. However, only S783 phosphorylation is evident in native tissue. S783 phosphorylation stabilizes GABAB receptors on the plasma membrane, thereby enhancing GIRK channel activity. The termination of S783 phosphorylation is due to dephosphorylation by protein phosphatase 2A (PP2A), which promotes clathrin-mediated endocytosis of GABAB receptors followed by proteasomal degradation. S892 phosphorylation by PKA enhances GABAB receptor cell surface stability, promotes potassium channel tetramerization domain-containing (KCTD) 12 (KCTD12) protein assembly with the R2 subunit and attenuates KCTD12-induced desensitization.

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