Chloride ions evoke taste sensations by binding to the extracellular ligand-binding domain of sweet/umami taste receptors

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Feb. 28, 2023

Salt taste sensation is multifaceted: NaCl at low or high concentrations preferably aversively perceived through distinct pathways. Cl − thought to participate in an unknown mechanism. Here, we describe ion binding and the response of receptor type 1 (T1r), a family composing sweet/umami receptors. The T1r2a/T1r3 heterodimer from medaka fish, currently sole T1r amenable structural analyses, exhibited specific vicinity amino-acid-binding site ligand-binding domain (LBD) T1r3, which likely conserved across species, including human T1r3. induced conformational change T1r2a/T1r3LBD sub- low-mM concentrations, similar canonical substances. Furthermore, oral application mice increased impulse frequencies nerves connected T1r-expressing cells promoted their behavioral preferences attenuated by T1r-specific blocker T1r3 knock-out. These results suggest that evokes sensations T1r, thereby serving as another preferred salt pathway concentration.

Language: Английский

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Cholesterol in Class C GPCRs: Role, Relevance, and Localization

Membranes, Journal Year: 2023, Volume and Issue: 13(3), P. 301 - 301

Published: March 3, 2023

G-protein coupled receptors (GPCRs), one of the largest superfamilies cell-surface receptors, are heptahelical integral membrane proteins that play critical roles in virtually every organ system. G-protein-coupled operate membranes rich cholesterol, with an imbalance cholesterol level within vicinity GPCR transmembrane domains affecting structure and/or function many GPCRs, a phenomenon has been linked to several diseases. These effects could result indirect changes by altering mechanical properties lipid environment or direct binding specific sites on protein. There number studies and reviews how modulates class A GPCRs; however, this area study is yet be explored for C which characterized large extracellular region often form constitutive dimers. This review highlights interaction, functions, structural dynamics involved recognition GPCRs. We summarize recent data from some typical family members explain features functions GPCRs speculate their corresponding therapeutic potential.

Language: Английский

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Constitutive activation mechanism of a class C GPCR

Nature Structural & Molecular Biology, Journal Year: 2024, Volume and Issue: 31(4), P. 678 - 687

Published: Feb. 8, 2024

Language: Английский

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Structural basis of positive allosteric modulation of metabotropic glutamate receptor activation and internalization

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 1, 2024

The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) to transmembrane (TMDs) drive intracellular signaling. Pharmacologically, mGluRs can be targeted at the LBDs by synthetic orthosteric compounds or TMDs allosteric modulators. Despite potential of therapeutics, an understanding functional structural basis their effects is limited. Here we use multiple approaches dissect versus ligands. We find, using electrophysiological live cell imaging assays, that both agonists positive modulators (PAMs) activation internalization group II III mGluRs. PAMs pleiotropic, boosting maximal response serving independently internalization-biased across mGluR subtypes. Motivated this intersubunit FRET analyses, determine cryo-electron microscopy structures mGluR3 in presence either agonist antagonist alone combination with a PAM. These reveal PAM-driven re-shaping intra- inter-subunit conformations provide evidence for rolling TMD dimer interface pathway controls beta-arrestin coupling. neuromodulator class GPCRs. Here, authors characterize ligand-evoked bias signaling motivate determination intermediate states.

Language: Английский

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Emerging modes of regulation of neuromodulatory G protein-coupled receptors

Trends in Neurosciences, Journal Year: 2024, Volume and Issue: 47(8), P. 635 - 650

Published: June 12, 2024

Language: Английский

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Mechanisms of differential desensitization of metabotropic glutamate receptors

Cell Reports, Journal Year: 2021, Volume and Issue: 35(4), P. 109050 - 109050

Published: April 1, 2021

G protein-coupled receptors (GPCRs) interact with intracellular transducers to control both signal initiation and desensitization, but the distinct mechanisms that regulation of different GPCR subtypes are unclear. Here we use fluorescence imaging electrophysiology examine metabotropic glutamate receptor (mGluR) family. We find properties across in rapid desensitization internalization, striking differences between group II mGluRs. mGluR3, not mGluR2, undergoes glutamate-dependent trafficking, recycling. map mGluRs variable Ser/Thr-rich sequences C-terminal domain (CTD) interaction kinases β-arrestins. Finally, identify a cancer-associated mutation, G848E, within mGluR3 CTD enhances β-arrestin coupling enabling an analysis β-arrestin-coupling revealing biased variants. Together, this work provides framework for understanding functional roles mGluR subtypes.

Language: Английский

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Amine-recognizing domain in diverse receptors from bacteria and archaea evolved from the universal amino acid sensor

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(42)

Published: Oct. 11, 2023

Bacteria possess various receptors that sense different signals and transmit information to enable an optimal adaptation the environment. A major limitation in microbiology is lack of on signal molecules activate receptors. Signals recognized by sensor domains are poorly reflected overall sequence identity, therefore, identification from amino acid alone presents a challenge. Biogenic amines great physiological importance for microorganisms humans. They serve as substrates aerobic anaerobic growth play role neurotransmitters osmoprotectants. Here, we report motif specific amine-sensing belong Cache superfamily most abundant extracellular sensors prokaryotes. We identified approximately 13,000 histidine kinases, chemoreceptors, involved second messenger homeostasis Ser/Thr phosphatases 8,000 bacterial archaeal species contain amine-recognizing motif. The screening compound libraries microcalorimetric titrations selected confirmed their ability specifically bind biogenic amines. Mutants amine-binding or single mismatch binding had either no largely reduced affinity demonstrate domain originated universal acid–sensing domain, thus providing insight into receptor evolution. Our approach enables precise “wet”-lab experiments define function regulatory systems therefore holds strong promise stimulating numerous

Language: Английский

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Distinct beta-arrestin coupling and intracellular trafficking of metabotropic glutamate receptor homo- and heterodimers

Science Advances, Journal Year: 2023, Volume and Issue: 9(49)

Published: Dec. 6, 2023

The metabotropic glutamate receptors (mGluRs) are family C, dimeric G protein–coupled (GPCRs), which play critical roles in synaptic transmission. Despite an increasing appreciation of the molecular diversity this family, how distinct mGluR subtypes regulated remains poorly understood. We reveal that different group II/III show markedly beta-arrestin (β-arr) coupling and endocytic trafficking. While mGluR2 is resistant to internalization mGluR3 shows transient β-arr coupling, enables endocytosis recycling, mGluR8 form stable complexes, leads efficient lysosomal targeting degradation. Using chimeras mutagenesis, we pinpoint carboxyl-terminal domain regions control trafficking, including identification splice variant with impaired internalization. then use a battery high-resolution fluorescence assays find heterodimerization further expands regulation. Together, work provides insight into relationship between GPCR/β-arr complex formation trafficking while revealing intricacy regulation mGluRs.

Language: Английский

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The impact of cryo-EM on determining allosteric modulator-bound structures of G protein-coupled receptors

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 79, P. 102560 - 102560

Published: Feb. 26, 2023

Language: Английский

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Molecular insights into the activation mechanism of GPR156 in maintaining auditory function

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Dec. 5, 2024

The class C orphan G-protein-coupled receptor (GPCR) GPR156, which lacks the large extracellular region, plays a pivotal role in auditory function through Gi2/3. Here, we firstly demonstrate that GPR156 with high constitutive activity is essential for maintaining function, and further reveal structural basis of sustained GPR156. We present cryo-EM structures human apo GPR156–Gi3 complex, unveiling small region formed by loop 2 (ECL2) N-terminus. dimer both state Gi3 protein-coupled adopt transmembrane (TM)5/6-TM5/6 interface, indicating state. Furthermore, C-terminus G-bound subunit dual promoting G protein binding within while preventing G-free from to additional protein. Together, these results explain how maintained dimerization provide mechanistic insight into function. has been identified as regulator hair cells. authors complex activation mechanism

Language: Английский

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