TMEM266 is a functional voltage sensor regulated by extracellular Zn2+

Papp, Ferenc; Lomash, Suvendu; Szilágyi, Orsolya; Babikow, Erika; Smith, Jaime J.; Chang, Tsun-Hsu; Bahamonde, María Isabel; Toombes, Gilman E. S.; Swartz, Kenton J.

doi:10.7554/elife.42372

Cited by 17 publications

(18 citation statements)

References 80 publications

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“…LRRC3B and MMP9 have been associated with mechanisms of cellular proliferation, invasion, and cell cycle regulation [ 53 , 54 ], and interestingly, LRRC3B has been shown to inhibit the expression of MMP9 in one study [ 55 ]. TMEM266 produces a functional voltage sensor at synapses in the cerebellum and thus may play important roles of neuronal signaling [ 56 , 57 ] while TENM2 appears to be involved in neuronal growth and migration [ 58 ]. BIN1 has been associated with neurodegenerative diseases [ 59 ] and may be involved in neuronal function [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Serious neonatal morbidities are associated with differences in DNA methylation among very preterm infants

et al. 2020

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Background Infants born very preterm are more likely to experience neonatal morbidities compared to their term peers. Variations in DNA methylation (DNAm) associated with these morbidities may yield novel information about the processes impacted by these morbidities. Methods This study included 532 infants born < 30 weeks gestation, participating in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants study. We used a neonatal morbidity risk score, which was an additive index of the number of morbidities experienced during the NICU stay, including bronchopulmonary dysplasia (BPD), severe brain injury, serious neonatal infections, and severe retinopathy of prematurity. DNA was collected from buccal cells at discharge from the NICU, and DNAm was measured using the Illumina MethylationEPIC. We tested for differential methylation in association with the neonatal morbidity risk score then tested for differentially methylated regions (DMRs) and overrepresentation of biological pathways. Results We identified ten differentially methylated CpGs (α Bonferroni-adjusted for 706,278 tests) that were associated with increasing neonatal morbidity risk scores at three intergenic regions and at HPS4, SRRD, FGFR1OP, TNS3, TMEM266, LRRC3B, ZNF780A, and TENM2. These mostly followed dose–response patterns, for 8 CpGs increasing DNAm associated with increased numbers of morbidities, while for 2 CpGs the risk score was associated with decreasing DNAm. BPD was the most substantial contributor to differential methylation. We also identified seven potential DMRs and over-representation of genes involved in Wnt signaling; however, these results were not significant after Bonferroni adjustment for multiple testing. Conclusions Neonatal DNAm, within genes involved in fibroblast growth factor activities, cellular invasion and migration, and neuronal signaling and development, are sensitive to the neonatal health complications of prematurity. We hypothesize that these epigenetic features may be representative of an integrated marker of neonatal health and development and are promising candidates to integrate with clinical information for studying developmental impairments in childhood.

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Section: Discussionmentioning

confidence: 99%

Serious neonatal morbidities are associated with differences in DNA methylation among very preterm infants

et al. 2020

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“…Voltage-gated proton channels (H V 1) exist in phylogenetically disparate species where they perform even more disparate functions, from calcification in coccolithophores (1) and mediating action potentials in bioluminescent dinoflagellates (2, 3), to numerous functions in various human tissues (4) such as compensating for electron flux in phagocytes (5–10) and enabling sperm capacitation (11). Identification of the gene (12, 13) revealed that H V 1 has 4 transmembrane helices, S1 to S4, and is homologous to the voltage-sensing domains (VSDs) present in most voltage-gated ion channels, voltage-sensing phosphatases, and TMEM266 (14). Unlike VSDs of other channels that sense voltage and cause a separate pore to open or close, H V 1 itself conducts protons (15), producing a direct readout of its gating state and making it a unique system for studying gating mechanisms.…”

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confidence: 99%

Hydrophobic gasket mutation produces gating pore currents in closed human voltage-gated proton channels

Banh

Cherny

Morgan

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The hydrophobic gasket (HG), a ring of hydrophobic amino acids in the voltage-sensing domain of most voltage-gated ion channels, forms a constriction between internal and external aqueous vestibules. Cationic Arg or Lys side chains lining the S4 helix move through this “gating pore” when the channel opens. S4 movement may occur during gating of the human voltage-gated proton channel, hHV1, but proton current flows through the same pore in open channels. Here, we replaced putative HG residues with less hydrophobic residues or acidic Asp. Substitution of individuals, pairs, or all 3 HG positions did not impair proton selectivity. Evidently, the HG does not act as a secondary selectivity filter. However, 2 unexpected functions of the HG in HV1 were discovered. Mutating HG residues independently accelerated channel opening and compromised the closed state. Mutants exhibited open–closed gating, but strikingly, at negative voltages where “normal” gating produces a nonconducting closed state, the channel leaked protons. Closed-channel proton current was smaller than open-channel current and was inhibited by 10 μM Zn2+. Extreme hyperpolarization produced a deeper closed state through a weakly voltage-dependent transition. We functionally identify the HG as Val109, Phe150, Val177, and Val178, which play a critical and exclusive role in preventing H+ influx through closed channels. Molecular dynamics simulations revealed enhanced mobility of Arg208 in mutants exhibiting H+ leak. Mutation of HG residues produces gating pore currents reminiscent of several channelopathies.

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“…Having a structural organization similar to animal Hvs is not sufficient to predict proton channel activity, as previously shown with HVRP1/TMEM266, a membrane protein closely related to human Hv1 that does not function as a channel 39 – 41 . So, we expressed the fungal proteins in Xenopus oocyte and performed electrophysiological measurements in excised membrane patches (Fig.…”

Section: Resultsmentioning

confidence: 95%

Voltage-gated proton channels from fungi highlight role of peripheral regions in channel activation

Zhao

Tombola

2021

Commun Biol

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Here, we report the identification and characterization of the first proton channels from fungi. The fungal proteins are related to animal voltage-gated Hv channels and are conserved in both higher and lower fungi. Channels from Basidiomycota and Ascomycota appear to be evolutionally and functionally distinct. Representatives from the two phyla share several features with their animal counterparts, including structural organization and strong proton selectivity, but they differ from each other and from animal Hvs in terms of voltage range of activation, pharmacology, and pH sensitivity. The activation gate of Hv channels is believed to be contained within the transmembrane core of the protein and little is known about contributions of peripheral regions to the activation mechanism. Using a chimeragenesis approach, we find that intra- and extracellular peripheral regions are main determinants of the voltage range of activation in fungal channels, highlighting the role of these overlooked components in channel gating.

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TMEM266 is a functional voltage sensor regulated by extracellular Zn2+

Cited by 17 publications

References 80 publications

Serious neonatal morbidities are associated with differences in DNA methylation among very preterm infants

Serious neonatal morbidities are associated with differences in DNA methylation among very preterm infants

Hydrophobic gasket mutation produces gating pore currents in closed human voltage-gated proton channels

Voltage-gated proton channels from fungi highlight role of peripheral regions in channel activation

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