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UNC-49 is a redox-sensitive GABA_A receptor that regulates the mitochondrial unfolded protein response cell nonautonomously.

ABSTRACT: The γ-aminobutyric acid-mediated (GABAergic) system participates in many aspects of organismal physiology and disease, including proteostasis, neuronal dysfunction, and life-span extension. Many of these phenotypes are also regulated by reactive oxygen species (ROS), but the redox mechanisms linking the GABAergic system to these phenotypes are not well defined. Here, we report that GABAergic redox signaling cell nonautonomously activates many stress response pathways in Caenorhabditis elegans and enhances vulnerability to proteostasis disease in the absence of oxidative stress. Cell nonautonomous redox activation of the mitochondrial unfolded protein response (mitoUPR) proteostasis network requires UNC-49, a GABA_A receptor that we show is activated by hydrogen peroxide. MitoUPR induction by a spinocerebellar ataxia type 3 (SCA3) C. elegans neurodegenerative disease model was similarly dependent on UNC-49 in C. elegans. These results demonstrate a multi-tissue paradigm for redox signaling in the GABAergic system that is transduced via a GABA_A receptor to function in cell nonautonomous regulation of health, proteostasis, and disease.

SUBMITTER: Pohl F

PROVIDER: S-EPMC10619936 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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UNC-49 is a redox-sensitive GABA<sub>A</sub> receptor that regulates the mitochondrial unfolded protein response cell nonautonomously.

Pohl Franziska F Germann Allison L AL Mao Jack J Hou Sydney S Bakare Bayode B Kong Thoo Lin Paul P Yates Kyari K Nonet Michael L ML Akk Gustav G Kornfeld Kerry K Held Jason M JM

Science advances 20231101 44

The γ-aminobutyric acid-mediated (GABAergic) system participates in many aspects of organismal physiology and disease, including proteostasis, neuronal dysfunction, and life-span extension. Many of these phenotypes are also regulated by reactive oxygen species (ROS), but the redox mechanisms linking the GABAergic system to these phenotypes are not well defined. Here, we report that GABAergic redox signaling cell nonautonomously activates many stress response pathways in <i>Caenorhabditis elegans ...[more]

PMID: 37910615

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Project description:(1) UNC-49B and UNC-49C are gamma-aminobutyric acid (GABA) receptor subunits encoded by the Caenorhabditis elegans unc-49 gene. UNC-49B forms a homomeric GABA receptor, or can co-assemble with UNC-49C to form a heteromeric receptor. The pharmacological properties of UNC-49B homomers and UNC-49B/C heteromers were investigated in Xenopus oocytes. (2) The UNC-49 subunits are most closely related to the bicuculline- and benzodiazepine-insensitive RDL GABA receptors of insects. Consistent with this classification, bicuculline (10 micro M) did not inhibit, nor did diazepam (10 micro M) enhance UNC-49B homomeric or UNC-49B/C heteromeric receptors. (3) The UNC-49C subunit strongly affects the pharmacology of UNC-49B/C heteromeric receptors. UNC-49B homomers were much more picrotoxin sensitive than UNC-49B/C heteromers (IC(50)=0.9+/-0.2 micro M and 166+/-42 micro M, respectively). Pentobarbitone enhancement was greater for UNC-49B homomers compared to UNC-49B/C heteromers. Propofol (50 micro M) slightly enhanced UNC-49B homomers but slightly inhibited UNC-49B/C heteromers. Penicillin G (10 mM) inhibited UNC-49B homomers less strongly than UNC-49B/C heteromers (30% compared to 53% inhibition, respectively). (4) Several aspects of UNC-49 pharmacology were unusual. Picrotoxin sensitivity strongly correlates with dieldrin sensitivity, yet UNC-49B homomers were highly dieldrin resistant. The enhancing neurosteroid pregnanolone (5beta-pregnan-3alpha-ol-20-one; 10 micro M) strongly inhibited both UNC-49 receptors. Alphaxalone (10 micro M), another enhancing neurosteroid, did not affect UNC-49B homomers, but slightly inhibited UNC-49B/C heteromers. (5) UNC-49 subunits and mammalian GABA(A) receptor alpha, beta, and gamma subunit classes all share roughly the same degree of sequence similarity. Thus, although they are most similar to other invertebrate GABA receptors, the UNC-49 receptors share significant structural and pharmacological overlap with mammalian GABA(A) receptors.

Dataset Information

UNC-49 is a redox-sensitive GABA_A receptor that regulates the mitochondrial unfolded protein response cell nonautonomously.

Publications

UNC-49 is a redox-sensitive GABA<sub>A</sub> receptor that regulates the mitochondrial unfolded protein response cell nonautonomously.

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Dataset Information

UNC-49 is a redox-sensitive GABAA receptor that regulates the mitochondrial unfolded protein response cell nonautonomously.

Publications

UNC-49 is a redox-sensitive GABA<sub>A</sub> receptor that regulates the mitochondrial unfolded protein response cell nonautonomously.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

UNC-49 is a redox-sensitive GABA_A receptor that regulates the mitochondrial unfolded protein response cell nonautonomously.