GABA receptors differentially regulate life span and health span in <i>C. elegans</i> through distinct downstream mechanisms

Yuan, Fengling; Zhou, Jiejun; Xu, Lingxiu; Jia, Wenhua; Lei, Chun; Xu, Xiangru; Liu, Jianfeng

doi:10.1152/ajpcell.00072.2019

Cited by 19 publications

(24 citation statements)

References 53 publications

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“…Previously, we also found that AgNPs coated with PVP could cause more severe oxidative stress and subacute toxicity at the same dose in mice compared with noncoated nanoparticles (Gan et al, 2020). Consistent with those findings, in the current study, we observed that both kinds of AgNPs induced a significant decrease in the survival rate of C. elegans (≥1 mg·L −1 ) either in 48 h or 6 days in a time‐ and dose‐dependent manner; nevertheless, PVP‐AgNPs caused more evident life losses, because the lifespan of C. elegans has complex regulatory mechanisms and GABAergic neurons are involved (Yuan et al, 2019). The study of the effects of AgNPs on the longevity of nematodes can help us better understand the long‐term toxicity and biological toxicity of AgNPs (Bayersdorf & Schumacher, 2019).…”

Section: Discussionsupporting

confidence: 90%

Neurobehavior and neuron damage following prolonged exposure of silver nanoparticles with/without polyvinylpyrrolidone coating in Caenorhabditis elegans

Zhang

et al. 2021

J of Applied Toxicology

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Silver nanoparticles (AgNPs) have become widespread in the environment with increasing industrial applications. But the studies about their potential health risks are far from enough, especially in neurotoxic effects. This study aimed to investigate the neurotoxic effects of longer‐term exposure (prolonged exposure for 48 h and chronic exposure for 6 days) of 20nm AgNPs with/without polyvinylpyrrolidone (PVP) coating at low concentrations (0.01–10 mg·L−1) to Caenorhabditis elegans. The results suggested that exposure to AgNPs induced damage to nematode survival, with the longest and relative average life span reduced. Exposure to AgNPs caused neurotoxicity on locomotion behaviors (head thrashes, body bends, pharyngeal pumping frequency, and defecation interval) and sensory perception behaviors (chemotaxis assay and thermotaxis assay), as well as impaired dopaminergic, GABAergic, and cholinergic neurons, except for glutamatergic, based on the alters fluorescence intensity, in a dose‐ and time‐dependent manner. Further investigations suggested that the low‐dose AgNPs (0.01–0.1 mg·L−1) exposure raises receptors of GABAergic and dopamine in C. elegans at the genetic level, whereas opposite results were observed at higher doses (1–10 mg·L−1), which implied that AgNPs could cause neurotoxicity by impairing neurotransmitter delivery. The PVP‐AgNPs could cause a higher fatality rate and neurotoxicity at the same dose. Notably, AgNPs did not cause any deleterious effect on nematodes at the lowest dose of 0.01 mg·L−1. In general, these results suggested that AgNPs possess the neurotoxic potential in C. elegans and provided useful information to understand the neurotoxicity of AgNPs, which would offer an inspiring perspective on the safe application.

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Section: Discussionsupporting

confidence: 90%

Neurobehavior and neuron damage following prolonged exposure of silver nanoparticles with/without polyvinylpyrrolidone coating in Caenorhabditis elegans

Zhang

et al. 2021

J of Applied Toxicology

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“…The UNC-30 pathway also controls genes that are involved in aging (Apfeld andKenyon, 1999, 2004;Jeong et al, 2012;Kenyon, 2010;Wolkow et al, 2000). The G proteincoupled GABA receptor GBB-1 modulates longevity through G protein-PLCb, which transmits longevity signals to FOXO/DAF-16 (Chun et al, 2015;Yuan et al, 2019). Our studies highlight a role for neural UNC-30 in the integration of signals that control the balance between the activation of both immune and longevity pathways that have opposite effects.…”

Section: Figure 6 Asg Neurons Control the Immunity-longevity Tradeoffmentioning

confidence: 78%

Immunity-longevity tradeoff neurally controlled by GABAergic transcription factor PITX1/UNC-30

Otarigho

Aballay

2021

Cell Reports

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A body of evidence indicates that metazoan immune and aging pathways are largely interconnected, but the mechanisms involved in their homeostatic control remain unclear. In this study, we find that the PITX (pairedlike homeodomain) transcription factor UNC-30 controls the tradeoff between immunity and longevity from the nervous system in Caenorhabditis elegans. PITX/UNC-30 functional loss enhances immunity in a GATA/ELT-2-and p38 MAPK/PMK-1-dependent manner and reduced longevity by activating MXD/MDL-1 and the C2H2-type zinc finger transcription factor PQM-1. The immune inhibitory and longevity stimulatory functions of PITX/UNC-30 require the sensory neuron ASG and a signaling pathway controlled by NPR-1, which is a G protein-coupled receptor related to mammalian neuropeptide Y receptors. Our findings uncover a suppressive role of GABAergic signaling in the neural control of a biological tradeoff where energy is allocated toward immunity at the expense of longevity.

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“…However, the structure of GABA B – G i1 complex coupling via GB1 demonstrates that GB1 couples to G i protein at certain circumstance. Indeed, GB1 in C. elegans directly couples to G i/o protein-dependent signaling 47,48 , indicating that GB1 retains the capacity for Gi protein coupling during evolution. Common activation mechanism for G protein activation by GPCRs has been proposed, in which the landmark of GPCR activation is the outwards movement of TM6 forming a cavity to accommodate the G proteins or β-arrestins, reflecting the convergence of activation pathways in class A, B and F GPCRs 43,49,50 .…”

Section: Resultsmentioning

confidence: 99%

Cryo-EM structures of inactive and G_i-coupled GABA_B heterodimer

Mao

Shen

et al. 2020

Preprint

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22Metabotropic GABA B G protein-coupled receptor functions as a mandatory heterodimer of 23 GB1 and GB2 subunits and mediates inhibitory neurotransmission in the central nervous system. 24Each subunit is composed of the extracellular Venus flytrap (VFT) domain and transmembrane 25 (TM) domain. Here we present cryo-EM structures of human full-length heterodimeric GABA B 26 receptor in the antagonist-bound inactive state and in the active state complexed with agonist 27 and positive allosteric modulator in the presence of G i1 protein at a resolution range of 2.8-3.0 28 Å. Cryo-EM analysis of the activated-GABA B -G i1 complex revealed that G i1 couples to the 29 activated receptor primarily in three major conformations, one via GB1 TM and two via GB2 30 TM, respectively. Our structures reveal that agonist binding stabilizes the closure of GB1 VFT, 31 which in turn triggers a rearrangement of TM interfaces between two subunits from TM3-32 TM5/TM3-TM5 in the inactive state to TM6/TM6 in the active state and finally induces the 33 opening of intracellular loop 3 and synergistically shifting of TM3, 4 and 5 helices in GB2 TM 34 domain to accommodate the α5-helix of G i1 . These results provide a structural framework for 35 understanding class C GPCR activation and a rational template for allosteric modulator design 36 targeting dimeric interface of GABA B receptor. 37 38 GABA B receptor belongs to the class C GPCR composed by metabotropic glutamate 54 receptors (mGlus), calcium-sensing receptor (CaSR) and taste 1 receptors 16 . Class C GPCR 55 form obligatory dimers, among them, mGlus and CaSR form the homodimer 17,18 , whereas 56 GABA B receptor is an obligatory heterodimer of two subunits GABA B1 (GB1) and GABA B2 57 (GB2) 19,20 . Each subunit is composed of a large extracellular 'Venus Flytrap' (VFT) domain, a 58 transmembrane (TM) domain, and a cytoplasmic tail 21 (Extended Data Fig. 1a, b). GB1 59 possesses an endoplasmic reticulum (ER) retention motif in its cytoplasmic tail 22 . The 60interaction between GB1 and GB2 facilitates its cell surface expression through coiled-coil 61 interactions in its cytoplasmic tail 23 . While GB1 is responsible for ligand recognition through 62 its VFT 24 , GB2 couples G i/o proteins through its TM 25,26 . However, a line of evidence show that 63 in the absence of GB2, GB1 asa (a GB1 mutant with deletion of ER retention signal) at the cell 64 surface or ER-localized GB1 also induces downstream signaling through G i/o proteins 27,28 . 65The crystal structures of isolated heterodimeric VFT of GABA B receptor in presence of the 66 antagonist or agonist revealed the open or closed conformation of GB1 VFT 29 . Structures of 67 isolated VFT and TM domains from other class C GPCR have been reported [30][31][32] , in addition to 68 more recently breakthrough that cryo-EM structures of full-length mGlu5 in apo state and in 69 the presence of agonist have been determined both at overall 4 Å resolution, providing the first 70 insights into the architecture of mGlu5 and structural framew...

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GABA receptors differentially regulate life span and health span in C. elegans through distinct downstream mechanisms

Cited by 19 publications

References 53 publications

Neurobehavior and neuron damage following prolonged exposure of silver nanoparticles with/without polyvinylpyrrolidone coating in Caenorhabditis elegans

Neurobehavior and neuron damage following prolonged exposure of silver nanoparticles with/without polyvinylpyrrolidone coating in Caenorhabditis elegans

Immunity-longevity tradeoff neurally controlled by GABAergic transcription factor PITX1/UNC-30

Cryo-EM structures of inactive and G_i-coupled GABA_B heterodimer

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GABA receptors differentially regulate life span and health span in C. elegans through distinct downstream mechanisms

Cited by 19 publications

References 53 publications

Neurobehavior and neuron damage following prolonged exposure of silver nanoparticles with/without polyvinylpyrrolidone coating in Caenorhabditis elegans

Neurobehavior and neuron damage following prolonged exposure of silver nanoparticles with/without polyvinylpyrrolidone coating in Caenorhabditis elegans

Immunity-longevity tradeoff neurally controlled by GABAergic transcription factor PITX1/UNC-30

Cryo-EM structures of inactive and Gi-coupled GABAB heterodimer

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Cryo-EM structures of inactive and G_i-coupled GABA_B heterodimer