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Hydrogen sulfide regulates hippocampal neuron excitability via S-sulfhydration of Kv2.1.

ABSTRACT: Hydrogen sulfide (H₂S) is gaining interest as a mammalian signalling molecule with wide ranging effects. S-sulfhydration is one mechanism that is emerging as a key post translational modification through which H₂S acts. Ion channels and neuronal receptors are key target proteins for S-sulfhydration and this can influence a range of neuronal functions. Voltage-gated K⁺ channels, including Kv2.1, are fundamental components of neuronal excitability. Here, we show that both recombinant and native rat Kv2.1 channels are inhibited by the H₂S donors, NaHS and GYY4137. Biochemical investigations revealed that NaHS treatment leads to S-sulfhydration of the full length wild type Kv2.1 protein which was absent (as was functional regulation by H₂S) in the C73A mutant form of the channel. Functional experiments utilising primary rat hippocampal neurons indicated that NaHS augments action potential firing and thereby increases neuronal excitability. These studies highlight an important role for H₂S in shaping cellular excitability through S-sulfhydration of Kv2.1 at C73 within the central nervous system.

SUBMITTER: Dallas ML

PROVIDER: S-EPMC8046973 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Hydrogen sulfide regulates hippocampal neuron excitability via S-sulfhydration of Kv2.1.

Dallas Mark L ML Al-Owais Moza M MM Hettiarachchi Nishani T NT Vandiver Matthew Scott MS Jarosz-Griffiths Heledd H HH Scragg Jason L JL Boyle John P JP Steele Derek D Peers Chris C

Scientific reports 20210414 1

Hydrogen sulfide (H2S) is gaining interest as a mammalian signalling molecule with wide ranging effects. S-sulfhydration is one mechanism that is emerging as a key post translational modification through which H2S acts. Ion channels and neuronal receptors are key target proteins for S-sulfhydration and this can influence a range of neuronal functions. Voltage-gated K+ channels, including Kv2.1, are fundamental components of neuronal excitability. Here, we show th ...[more]

PMID: 33854181

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Project description:The deacetylase SIRT1 (sirtuin 1) has emerged as a major regulator of nucleocytoplasmic distribution of macroautophagy/autophagy marker MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3). Activation of SIRT1 leads to the deacetylation of LC3 and its translocation from the nucleus into the cytoplasm leading to an increase in the autophagy flux. Notably, hydrogen sulfide (H2S) is a cytoprotective gasotransmitter known to activate SIRT1 and autophagy; however, the underlying mechanism for both remains unknown. Herein, we demonstrate that H2S sulfhydrates the active site cysteine of the glycolytic enzyme GAPDH (glyceraldehyde-3-phosphate dehydrogenase). Sulfhydration of GAPDH leads to its redistribution into the nucleus. Importantly, nuclear localization of GAPDH is critical for H2S-mediated activation of autophagy as H2S does not induce autophagy in cells with GAPDH ablation or cells overexpressing a GAPDH mutant lacking the active site cysteine. Importantly, we observed that nuclear GAPDH interacts with CCAR2/DBC1 (cell cycle activator a nd apoptosis regulator 2) inside the nucleus. CCAR2 interacts with the deacetylase SIRT1 to inhibit its activity. Interaction of GAPDH with CCAR2 disrupts the inhibitory effect of CCAR2 on SIRT1. Activated SIRT1 then deacetylates MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) to induce its translocation into the cytoplasm and activate autophagy. Additionally, we demonstrate this pathway's physiological role in autophagy-mediated trafficking of Mycobacterium tuberculosis into lysosomes to restrict intracellular mycobacteria growth. We think that the pathway described here could be involved in H2S-mediated clearance of intracellular pathogens and other health benefits.Abbreviations: ATG5: autophagy related 5; ATG7: autophagy related 7; BECN1: beclin 1, autophagy related; CCAR2/DBC1: cell cycle activator and apoptosis regulator 2; CFU: colony-forming units; DLG4/PSD95: discs large MAGUK scaffold protein 4; EX-527: 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; H2S: hydrogen sulfide; HEK: human embryonic kidney cells; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; Mtb: Mycobacterium tuberculosis; MTOR: mechanistic target of rapamycin kinase; MOI: multiplicity of infection; NO: nitric oxide; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; PLA: proximity ligation assay; PRKAA: protein kinase, AMP-activated, alpha catalytic subunit; SIAH1: siah E3 ubiquitin protein ligase 1A; SIRT1: sirtuin 1; TB: tuberculosis; TP53INP2/DOR: transformation related protein 53 inducible nuclear protein 2; TRP53/TP53: transformation related protein 53.

Dataset Information

Hydrogen sulfide regulates hippocampal neuron excitability via S-sulfhydration of Kv2.1.

Publications

Hydrogen sulfide regulates hippocampal neuron excitability via S-sulfhydration of Kv2.1.

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