Kaulich E , McCubbin PTN , Schafer WR , Walker DS .

MC_U105185857 Medical Research Council , R01 NS110391 NINDS NIH HHS , R21 DC015652 NIDCD NIH HHS , WT103784MA Wellcome Trust , Wellcome Trust

	Figure 1. Phylogram of the DEG/ENaC familyPolar view of a phylogram of the DEG/ENaC superfamily; protein sequences were aligned in MAFFT version 7 (see Methods for details). Tree scale represents the amount of genetic change. The data used to build these networks originate from the UniProt Consortium databases and the InterPro and ENA databases from EMBL‐EBI. Colouring is according to phyla, as indicated. Accession numbers can be found in Table 2. Lower case letters indicate species of one group, i.e. for Chordata, z indicates zebrafish (Danio rerio) and r indicates rat (Rattus norvegicus), for Annelida p indicates Platynereis dumerilii, Lg for Lottia gigantean, Ls for Lymnaea stagnalis, Ha for Helix aspersa and Ht for Helisoma trivolvis. C. elegans names reflect homology or phenotype of mutants. ACD, acid‐sensitive degenerin; ASIC, acid‐sensing ion channel; DEG, degenerin; DEL, degenerin like; DELM, degenerin linked to mechanosensation; EGAS, EGF plus ASC domain ion channel; ENaC, epithelial sodium channel; FaNaC, FMRFamide‐gated sodium channel; FLR, fluoride resistant; ; HyNaC, Hydra sodium channel; MEC, mechanosensory abnormality; PPK, Pickpocket; TadNaC, Trichoplax adhaerens sodium channel; UNC, uncoordinated. [Colour figure can be viewed at wileyonlinelibrary.com]
	Figure 2. Sequence similarity network (SSN) of the DEG/ENaC familySSN of diverse members of the DEG/ENaC family. Generated using the web tool for SSNs for protein families (EFI‐EST) developed by the Enzyme Function Initiative efi.igb.illinois.edu/ (Gerlt et al., 2015; Gerlt, 2017; Zallot et al., 2018; Zallot et al., 2019). Each symbol represents a protein (node), two nodes are connected by a line (edge) if they share > 25% sequence similarity and lengths of edges correlate with the relative dissimilarities of each pair. Relative positioning of disconnected clusters and nodes has no meaning. Unconnected notes, i.e. nodes with a degree of zero, are indicated on the bottom right‐hand side. Cytoscape (Shannon et al., 2003) was used to explore SSNs. Node sizes are determined by the degree of connectivity of the nodes (number of edges). The EFI‐EST webtools use NCBI BLAST and CD‐HIT to create SSNs. The computationally guided functional profiling tool uses the CGFP programs from the Balskus Lab (https://www.microbialchemist.com/metagenomic‐profiling/) (Levin et al., 2017) and ShortBRED from the Huttenhower Lab (http://huttenhower.sph.harvard.edu/shortbred) (Kaminski et al., 2015). The data used to build these networks originated from the UniProt Consortium databases and the InterPro and ENA databases from EMBL‐EBI. Node colouring is according to phyla, as indicated. Accession numbers can be found in Table 2. [Colour figure can be viewed at wileyonlinelibrary.com]
	Figure 3. Quantification of current at pH 7.4 and pH 4 of Xenopus oocytes expressing C. elegans DEG/ENaC subunitsGraphs show raw current upon perfusion with either pH 7.4 (filled circle) or pH 4 (open circle) as indicated, for Xenopus oocytes injected with the respective cRNA. Lines connect data from individual oocytes. A, nuclease free water‐injected oocytes serve as negative controls (N = 13). B, ACD‐1 (n = 8) expressing oocytes serve as a positive control (Wang et al., 2008). C, constructs that form acid‐activated channels: ACD‐2 (N = 13), ASIC‐1 (N = 7) and DEL‐9 (N = 19). D, constructs that form acid‐inhibited channels: ACD‐5 (N = 5), DEL‐4 (N = 9), DELM‐1 (N = 7) and UNC‐105 (N = 17). The pH‐insensitive currents of FLR‐1, ACD‐3 and DEL‐5 are published elsewhere (Kaulich et al., 2022). For the remaining 19 DEG/ENaC subunits that did not display acid‐sensitive currents, see ‘Statistical summary document’. Holding potential was −60 mV. Experiments were repeated on more than three different days, with different oocyte batches, and were pooled together. Note that all graphs are plotted using the same scale, except ASIC‐1 and DELM‐1 due to the large currents observed in oocytes expressing these two constructs. Results of statistical tests are shown above graphs. Top row: comparison with water‐injected control, at pH 7.4 and 4.0, respectively; bottom row: comparison between pH 7.4 and pH 4.0. P‐values, listed in the order shown, left to right, top to bottom, for each subunit: ACD‐1 (<0.0001, >0.9999, 0.0037), ACD‐2 (0.0004, 0.0037, 0.0002), ASIC‐1 (>0.9999, 0.0051, <0.0001), DEL‐9 (0.0102, 0.0005, <0.0001), ACD‐5 (0.0004, 0.6178, 0.0193), DEL‐4 (<0.0001, >0.9999, 0.0025) DELM‐1 (0.2448, >0.9999, 0.1608), UNC‐105 (0.3270, >0.9999, 0.0044). Asterisks indicate significance level, **** <0.0001, *** <0.001, ** <0.01, * <0.05.
	Figure 4. DELM‐1 and UNC‐105 form acid‐inhibited homomeric cation channels A, representative traces of Xenopus oocytes expressing the respective construct when perfused with solutions of different pH (black bar) from a pre‐stimulus holding pH of 7.4. B, current–pH relationship. Dotted line indicates pH50. DELM‐1, pH50 = 5.1 (SD = 0.22, N = 11); and DELM‐1 co‐expressed with DELM‐2, pH50 = 5.0 (SD = 0.28, N = 21), Global comparison of fits (extra sum‐of‐squares F‐test) showed that the pH50 values of both datasets are the same P = 0.93. UNC‐105 isoform h, pH50 = 6.30 (SD = 0.39, N = 15). Currents were recorded at a holding potential of –60 mV, baseline subtracted using pre‐stimulus current and drift corrected, then normalised to maximal/maximal currents and best fitted with the Hill equation (variable slope). Data points and error bars represent mean (SD). C, average calculated from N = 6 oocytes of ΔE rev when shifting from a NaCl solution to KCl or LiCl solution. A negative shift of E rev indicates a preference for Na+ over the respective ion and a positive shift indicates a preference of the respective ion over Na+. Data are presented as box‐plots (hinges of the plot are the 25th and 75th percentiles) with median and whiskers of minimum and maximum. D, representative current–voltage (I–V) relationships for oocytes expressing UNC‐105h. Currents are baseline subtracted with Roboocyte2+ software. The oocyte membrane was clamped at −60 mV and voltage steps from −150 to +75 mV were applied as indicated. Currents in µA (y‐axis), voltage steps in mV (x‐axis) as indicated. [Colour figure can be viewed at wileyonlinelibrary.com]
	Figure 5. ASIC‐1, ACD‐2 and DEL‐9 form acid‐activated homomeric channels permeable to monovalent cations A, representative traces of Xenopus oocytes expressing the respective construct when perfused with solutions of different pH, lowering the pH from a holding pH of 7.4. B, current–pH relationship. Dotted line indicates pH50. ASIC‐1, pH50 = 4.50 (SD = 0.08, N = 13); ACD‐2, pH50 = 5.04 (SD = 0.22, N = 6); DEL‐9, pH50 = 4.33 ± 0.22 (N = 10). Currents were recorded at a holding potential of –60 mV; baseline subtracted using pre‐stimulus current and drift corrected, then normalised to maximal currents (I/I max) and best fitted with the Hill equation (variable slope). Data points and error bars represent mean (SD). C and D, summary of ion selectivity. ASIC‐1, ACD‐2 and DEL‐9 are permeable to monovalent cations. C, average calculated from 4 < N < 12 oocytes for each construct of ΔE rev when shifting from a NaCl solution to KCl or LiCl solution. A negative shift of E rev indicates a preference for Na+ over the respective ion and a positive shift indicates a preference of the respective ion over Na+. Data are presented as box‐plots (hinges of the plot are the 25th and 75th percentiles) with median and whiskers of minimum and maximum. D, representative current–voltage (I–V) relationships for oocytes expressing ASIC‐1, ACD‐2 and DEL‐9. Currents are baseline subtracted with Roboocyte2+ software. For acid‐evoked current at pH50 concentrations, see panel B for reference. The oocyte membrane was clamped at −60 mV and voltage steps from −150 to +75 mV were applied as indicated. Currents in µA (y‐axis), voltage steps in mV (x‐axis) as indicated. [Colour figure can be viewed at wileyonlinelibrary.com]
	Figure 6. Concentration‐dependent acid‐sensitive currents and ΔGAS belt deletion of UNC‐105h and DEL‐9 channels A and B, baseline‐subtracted peak currents of oocytes expressing DEL‐9 (A) and UNC‐105 (B) at varying concentrations (0 ng/µl, nuclease‐water injected controls), recorded at pH50 concentration for DEL‐9 (see Fig. 4B for pH50) and at pH 7.4 for UNC‐105h). Number of oocytes: N DEL‐9 (left to right) = 10, 11, 16, 14; and N UNC‐105h (left to right) = 15, 21, 21, 15. A one‐way‐ANOVA with post hoc test (Bonferroni correction) was conducted between the different concentrations, indicated are the P‐values. Currents in nA (y‐axis), concentration of injected cRNA in ng/µl (x‐axis) as indicated. C and D, baseline subtracted currents of DEL‐9 wild‐type (N = 11 oocytes) and DEL‐9 (ΔGAS‐belt) (N = 10 oocytes) (injected at 500 ng/µl) at pH 7.4 and pH 4.25. E and F, baseline subtracted peak currents of UNC‐105h wild‐type (N = 20 oocytes) and UNC‐105h (ΔGAS‐belt) (N = 29 oocytes) (injected at 500 ng/µl) at pH 7.4 and pH 5. The oocyte membrane was clamped at −60 mV. Currents in nA (y‐axis), pH (x‐axis) as indicated. For DEL‐9, currents were baseline subtracted using pre‐stimulus current (i.e. at pH 7.4), then drift corrected, using Roboocyte2+ software; for UNC‐105, this was baseline adjusted using the pH 5 current (since current is minimal at pH 5; Fig. 4B ). [Colour figure can be viewed at wileyonlinelibrary.com]
	Figure 7. Amiloride‐sensitivity of acid‐activated channels ACD‐2, ASIC‐1 and DEL‐9 at pH50 ASIC‐1 and ACD‐2 (but not DEL‐9) acid‐evoked transient currents can be blocked by amiloride. Representative acid‐evoked transient currents in the absence (left) and presence of 500 µM amiloride (middle) at pH50 (for pH50 of each channel see Fig. 5B ), and amiloride dose–response curves (right). A, nuclease‐free water‐injected oocytes (negative control) are unaffected by low pH (example shown here pH 4.5) or amiloride. B and C, amiloride dose response of ASIC‐1 with an IC50 of 108 µM amiloride (SD = 43, N = 10) (B) and ACD‐2 with an IC50 of 87 µM amiloride (SD = 41, N = 12) (C). D, DEL‐9 (N = 3) acid‐activated transient currents are unaffected by amiloride. The Xenopus oocyte membrane was clamped at −60 mV and voltage steps from −150 to +75 mV were applied as indicated. Raw currents in µA (y‐axis), voltage steps in mV (x‐axis) as indicated. Data points and error bars represent mean (SD). Currents were recorded at a holding potential of −60 mV. For dose responses, currents were baseline subtracted (i.e. zero indicates the pre‐stimulus (pH 7.4) current), then normalised to the maximum current (I max) calculated for each oocyte individually, and best fitted with the Hill equation (variable slope). [Colour figure can be viewed at wileyonlinelibrary.com]
	Figure 8. The effect of amiloride on acid‐sensitive DEG/ENaCs at pH 7.4Representative transient currents in the absence (left) and presence of 500 µM amiloride (middle), and current–voltage (I–V) relationships (right) at pH 7.4. A, ACD‐1 and DELM‐1 (positive controls). B, ACD‐2, ACD‐5, DEL‐4, DEL‐10 and UNC‐105h transient currents can be blocked by amiloride. C, DEL‐9 transient currents at pH 7.4 are potentiated in the presence of amiloride. Xenopus oocytes are perfused with a basal solution (ND96) only (filled circles), and in presence of the DEG/ENaC channel blocker amiloride (open circles). Scales vary between constructs due to the variability in the amplitude of the currents. The oocyte membrane was clamped at −60 mV and voltage steps from −150 to +75 mV were applied as indicated. Raw currents in µA (y‐axis), voltage steps in mV (x‐axis) as indicated. Data points and error bars represent mean and SD, and N is number of individual oocytes tested in independent experiments pooled together.
	Figure 9. Paradoxical effect of amiloride on UNC‐105htransient currents at pH 7.4 can be blocked by amiloride. A, representative transient currents at increasing concentrations of amiloride. Amiloride blocks the channel at 1 µM concentration but other concentrations do not affect the currents. The Xenopus oocyte membrane was clamped at −60 mV. Raw currents in µA (y‐axis), voltage steps in mV (x‐axis) as indicated. B, amiloride dose response of UNC‐105 with an IC50 of 0.76 µM amiloride (SD = 0.49) and EC50 of 5.9 µM amiloride (SD = 0.18). N = 7. Currents were recorded at a holding potential of −60 mV, baseline subtracted using pre‐stimulus current and drift corrected, then normalised to the maximum current (I max) calculated for each oocyte individually, and best fitted with the Hill equation (variable slope). Data points and error bars represent mean (SD). [Colour figure can be viewed at wileyonlinelibrary.com]
	Figure 10. Zinc modulation of acid‐activated DEG/ENaC channels in Xenopus oocytes at pH50 Zn2+ can block homomeric ASIC‐1, ACD‐2 and DEL‐9 acid‐evoked currents. Shown are representative example traces (left) and dose response curves (right) for each channel. ASCI‐1 (A), ACD‐2 (B) and DEL‐9 (C) pH50‐evoked transient currents can be blocked by Zn2+ in a dose‐dependent manner (at pH50 of each channel). Zn2+ dose response of ASIC‐1 with an IC50 of 284 µM Zn2+ (SD = 131, N = 10), ACD‐2 with an IC50 of 51 µM Zn2+ (SD = 18, N = 15) and DEL‐9 with an IC50 of 23 µM Zn2+ (SD = 19, N = 13). Baseline subtraction (using the pre‐stimulus current, i.e. at pH 7.4) and drift correction was applied with Roboocyte2+ software. Currents were recorded at a holding potential of −60mV and are normalised to the maximum current (I max) calculated for each oocyte individually, and best fitted with the Hill equation (variable slope). Data points and error bars represent mean (SD). The black bar indicates perfusion of the respective Zn2+ concentration. [Colour figure can be viewed at wileyonlinelibrary.com]
	Figure 11. Zinc modulation of acid‐inhibited DEG/ENaC channels in Xenopus oocytes at pH 7.4 A–E, Zn2+ modulates homomeric ACD‐1, ACD‐5, DELM‐1, DEL‐4, and UNC‐105 currents at pH 7.4 in a dose‐dependent manner. Shown are representative example traces (Left) and dose–response curves (right) for each channel: Zn2+ dose response of ACD‐1 with an IC50 of 208 µM (SD = 100, N = 7) Zn2+, ACD‐5 with an IC50 of 0.19 µM (SD = 0.05, N = 4) and an EC50 of 1251 µM (SD = 433, N = 4), DELM‐1 with an EC50 of 262 µM (SD = 136, N = 4), DEL‐4 with an IC50 of 12 µM (SD = 5, N = 5), and UNC‐105h with an IC50 of 31 µM (SD = 11, N = 4) Zn2+. Baseline subtraction and drift correction was applied with Roobocye2+ software. Currents were recorded at a holding potential of −60 mV and are normalised to the maximum current (I max) calculated for each oocyte individually, and best fitted with the Hill equation (variable slope). Data points and error bars represent mean (SD). The black bar indicates perfusion of the respective Zn2+ concentration. [Colour figure can be viewed at wileyonlinelibrary.com]
	Figure 12. Acid‐activated DEG/ENaCs are expressed in neuronal and non‐neuronal tissueExpression pattern of the transcriptional promoter fusions of the acid‐activated DEG/ENaC genes with mKate2 or GFP in L4 and young adults. A, the asic‐1 promoter drives expression in the dopaminergic neurons and PVDs and FLPs. B, acd‐2 promoter expression can be faintly detected in the head, which based on localisation and RNA‐sequencing data by Cao et al. (2017) could be neurons or glia cells. Green dots in the intestine are autofluorescence. C, The del‐9 promoter drives expression in the body‐wall and egg‐laying muscles, in head neurons, PVQ neuron and the GABAergic neuron AVL. Pink asterisks indicate the coelomocytes (Punc‐122::GFP, used as co‐injection marker to select transgenic animals). Scale bars: 100 µm (A), 10 µm (B) and 100 µm (C). Orientation indicator shown top right, A, anterior; D, dorsal; P, posterior; V, ventral. [Colour figure can be viewed at wileyonlinelibrary.com]

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