Structural biology of GABAB receptor

Frangaj, Aurel; Fan, Qing

doi:10.1016/j.neuropharm.2017.10.011

Cited by 80 publications

(64 citation statements)

References 140 publications

(344 reference statements)

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“…GABAB receptor [20]). Despite its probable mislocalization, we presume that the folding of σ1R should only be modestly affected by the N-terminal tagging because of the preserved binding pocket considering the only lightly-affected Kd compared to that of the unmodified construct.…”

mentioning

confidence: 99%

The effects of terminal tagging on homomeric interactions of the sigma 1 receptor

Yano

Liu

Naing

et al. 2019

Preprint

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The sigma 1 receptor (σ1R) has been implicated in cancers, neurological disorders, and substance use disorders. Yet, its molecular and cellular functions have not been well-understood.Recent crystal structures of σ1R reveal a single N-terminal transmembrane segment and Cterminal ligand-binding domain, and a trimeric organization. Nevertheless, outstanding issues surrounding the functional or pharmacological relevance of σ1R oligomerization remain, such as the minimal protomeric unit and the differentially altered oligomerization states by different classes of ligands. Western blot (WB) assays have been widely used to investigate protein oligomerizations. However, the unique topology of σ1R renders several intertwined challenges in WB. Here we describe a WB protocol without temperature denaturization to study the ligand binding effects on the oligomerization state of σ1R. Using this approach, we observed unexpected ladder-like incremental migration pattern of σ1R, demonstrating preserved homomeric interactions in the detergent environment. We compared the migration patterns of intact σ1Rconstruct and the C-terminally tagged σ1R constructs, and found similar trends in response to drug treatments. In contrast, N-terminally tagged σ1R constructs show opposite trends to that of the intact construct, suggesting distorted elicitation of the ligand binding effects on oligomerization.Together, our findings indicate that the N-terminus plays an important role in eliciting the impacts of bound ligands, whereas the C-terminus is amenable for modifications for biochemical studies.

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mentioning

confidence: 99%

The effects of terminal tagging on homomeric interactions of the sigma 1 receptor

Yano

Liu

Naing

et al. 2019

Preprint

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“…3b, c). Additionally, a conserved TM6 tryptophan, which acts as an activating "toggle-switch" in other Family C GPCRs 28,29 , is replaced by cysteine residues in both GABAB1 and GABAB2 receptors (Supplemental Figs. 4c,d).…”

Section: Supplemental Figs 6b-d)mentioning

confidence: 99%

Structures of metabotropic GABA_Breceptor

Papasergi-Scott

Robertson

Seven

et al. 2020

Preprint

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GABA (γ-aminobutyric acid) stimulation of the metabotropic GABAB receptor results in prolonged inhibition of neurotransmission that is central to brain physiology. GABAB belongs to the Family C of G protein-coupled receptors (GPCRs), which operate as dimers to relay synaptic neurotransmitter signals into a cellular response through the binding and activation of heterotrimeric G proteins. GABAB, however, is unique in its function as an obligate heterodimer in which agonist binding and G protein activation take place on distinct subunits. Here we show structures of heterodimeric and homodimeric full-length GABAB receptors. Complemented by cellular signaling assays and atomistic simulations, the structures reveal an essential role for the GABAB extracellular loop 2 (ECL2) in relaying structural transitions by ordering the linker connecting the extracellular ligand-binding domain to the transmembrane region. Furthermore, the ECL2 of both GABAB subunits caps and interacts with the hydrophilic head of a phospholipid occupying the extracellular half of the transmembrane domain, thereby providing a potentially crucial link between ligand binding and the receptor core that engages G protein. These results provide a starting framework to decipher mechanistic modes of signal transduction mediated by GABAB dimers and have important implications for rational drug design targeting these receptors.

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“…GABA B receptors (GBRs) are G protein‐coupled receptors for the main inhibitory neurotransmitter in the central nervous system, γ‐aminobutyric acid (GABA) . The GABA metabolite γ‐hydroxybutyrate (GHB), a psychoactive drug of abuse, is a second endogenous ligand of GBRs .…”

Section: Gbr Functions In the Brainmentioning

confidence: 99%

“…However, GBRs clearly mediate most of the physiological effects observed with recreational use of GHB. GBRs activate heterotrimeric Gi/o‐type G proteins that inhibit adenylyl cyclase through the Gα subunit . The consequences of inhibiting cAMP production in neurons through GBRs include the inhibition of spontaneous neurotransmitter release and the disinhibition of two‐pore domain K + channels .…”

Section: Gbr Functions In the Brainmentioning

confidence: 99%

“…A large body of evidence supports that GB1 and GB2 assume distinct and non‐redundant functions in the heterodimeric receptor. Most notably, GB1 binds GABA while GB2 couples to the G protein and increases GABA affinity at GB1 . Allosteric interactions between GB1 and GB2 are therefore necessary for activating the G protein at GB2 after binding of GABA to GB1 .…”

Section: Functions Of Obligate Receptor Componentsmentioning

confidence: 99%

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The organizing principle of GABA_B receptor complexes: Physiological and pharmacological implications

Fritzius

Bettler

2019

Basic Clin Pharma Tox

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GABAB receptors (GBRs), the G protein‐coupled receptors for the neurotransmitter γ‐aminobutyric acid (GABA), regulate synaptic transmission at most synapses in the brain. Proteomic approaches revealed that native GBR complexes assemble from an inventory of ~30 proteins that provide a molecular basis for the functional diversity observed with these receptors. Studies with reconstituted GBR complexes in heterologous cells and complementary knockout studies have allowed to identify cellular and physiological functions for obligate and several non‐obligate receptor components. It emerges that modular association of receptor components in space and time generates a variety of multiprotein receptor complexes with different localizations, kinetic properties and effector channels. This article summarizes current knowledge on the organizing principle of GBR complexes. We further discuss unanticipated receptor functions, links to disease and opportunities for drug discovery arising from the identification of novel receptor components.

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Structural biology of GABAB receptor

Cited by 80 publications

References 140 publications

The effects of terminal tagging on homomeric interactions of the sigma 1 receptor

The effects of terminal tagging on homomeric interactions of the sigma 1 receptor

Structures of metabotropic GABA_Breceptor

The organizing principle of GABA_B receptor complexes: Physiological and pharmacological implications

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Structural biology of GABAB receptor

Cited by 80 publications

References 140 publications

The effects of terminal tagging on homomeric interactions of the sigma 1 receptor

The effects of terminal tagging on homomeric interactions of the sigma 1 receptor

Structures of metabotropic GABABreceptor

The organizing principle of GABAB receptor complexes: Physiological and pharmacological implications

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Product

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Structures of metabotropic GABA_Breceptor

The organizing principle of GABA_B receptor complexes: Physiological and pharmacological implications