N-Glycosylation of TREK-1/hK2P2.1 Two-Pore-Domain Potassium (K2P) Channels
"> Figure 1
<p>hTREK-1 channels harbor two putative <span class="html-italic">N</span>-glycosylation sites. (<b>a</b>) Two potential <span class="html-italic">N</span>-glycosylation consensus sites (yellow), consisting of an asparagine residue (N, red) followed by any amino acid except proline (x) and a serine or threonine residue (S/T, red) can be found in the extracellular part of the hTREK-1 amino acid sequence. Asparagine residues possibly modified by carbohydrates are located in positions 110 and 134. (<b>b</b>) Depicts a schematic membrane topology model of a hTREK-1 channel monomer consisting of two pore-forming loops (P1 and P2) surrounded by four transmembrane domains (M1–M4; top: extracellular space, bottom: intracellular space). Both potential <span class="html-italic">N</span>-glycosylation motifs are located in the extracellular M1-P1 interdomain. (<b>c</b>) Three-dimensional model of a hTREK-1 channel dimer, based on its crystal structure (PDB ID: 4TWK) [<a href="#B40-ijms-20-05193" class="html-bibr">40</a>,<a href="#B41-ijms-20-05193" class="html-bibr">41</a>,<a href="#B42-ijms-20-05193" class="html-bibr">42</a>]. N110 is located at the top of the overhead domain, and N134 is situated at a more lateral position. (<b>d</b>) A partial sequence alignment comparing hTREK-1 protein sequences of different species showing conservation of both motifs (‘*’, full conservation; ‘:’, conservative substitution; ‘.’, semiconservative substitution). (<b>e</b>) Immunoblot of hTREK-1-1d4 channel subunits heterologously expressed in <span class="html-italic">Xenopus laevis</span> oocytes. After coinjection of the antibiotic <span class="html-italic">N</span>-glycosylation inhibitor tunicamycin (TM), hTREK-1-1d4 proteins display increased electrophoretic mobility. The signals of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) are provided as loading controls.</p> "> Figure 2
<p>Inhibition of <span class="html-italic">N</span>-glycosylation by tunicamycin decreases TREK-1 currents. (<b>a</b>) The TREK-1 currents elicited by a 500 ms depolarizing voltage step from −80 mV to +20 mV (see depicted pulse protocol) are displayed under control conditions (CTRL) and 48 h after administration of TM by incubation (left) or cytoplasmic injection (right). Representative recording of <span class="html-italic">n</span> = 6–12 cells. (<b>b</b>) The mean potassium currents at +20 mV (top) and the resting membrane potentials (RMPs, bottom) are provided for different time points (24 h, black bars; 48 h, white bars) after TM incubation (left; <span class="html-italic">n</span> = 3–15) or cytoplasmic injection (right; <span class="html-italic">n</span> = 3–15 cells). (<b>c</b>) Representative families of macroscopic hTREK-1 potassium currents recorded from <span class="html-italic">Xenopus laevis</span> oocytes by application of the depicted pulse protocol. (<b>d</b>) Corresponding mean step current amplitudes plotted as functions of the test pulse potential showing comparable current-voltage relationships under control conditions and after application of TM. Inserts: the data are presented relative to the maximum current amplitude measured at +60 mV. The data are given as the mean ± standard error of the mean (SEM). The zero-current levels are indicated by dashed lines. The pulse protocols are depicted below the respective current traces. * <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01.</p> "> Figure 3
<p>Molecular biological disruption of hTREK-1 <span class="html-italic">N</span>-glycosylation. (<b>a</b>) <span class="html-italic">N</span>-glycosylation can be disrupted either by introducing a proline residue in position +3 relative to the <span class="html-italic">N</span>-glycosylation acceptor residue (<b>a</b>,<b>c</b>,<b>e</b>,<b>g</b>,<b>i</b>) or by substituting the carbohydrate acceptor asparagine to glutamine (<b>b</b>,<b>d</b>,<b>f</b>,<b>h</b>,<b>j</b>). (<b>a</b>,<b>b</b>) Protein lysates of <span class="html-italic">Xenopus laevis</span> oocytes injected with RNA of the indicated hTREK-1-1d4 mutant constructs lacking the first, the second or both the first and second <span class="html-italic">N</span>-glycosylation motifs were subjected to immunoblotting. Changes in carbohydrate modifications are displayed as altered electrophoretic mobility. Please note that the E113P substitution resulted in incomplete disruption of <span class="html-italic">N</span>-glycosylation at N110. The immunosignals of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) are given as loading controls. (<b>c</b>,<b>d</b>) Representative current traces recorded from <span class="html-italic">Xenopus laevis</span> oocytes expressing the indicated hTREK-1 variants after 24 h (left) or 48 h (right). The currents were evoked by the application of depolarizing voltage steps from −80 mV to +20 mV. Representative current traces of <span class="html-italic">n</span> = 4–12 cells are shown. The mean current amplitudes (top) and resting membrane potentials (bottom) of the cells included in this experiment are displayed in (<b>e</b>,<b>f</b>). (<b>g</b>,<b>h</b>) Families of hTREK-1 current traces evoked by the displayed pulse step protocols 48 h after injection of the hTREK-1 WT or mutant construct. (<b>i</b>,<b>j</b>) Activation curves recorded under isochronal conditions 48 h after RNA injection. Inserts: the data presented relative to the maximum current amplitude measured at +60 mV display comparable voltage-current relationships between glycosylated and nonglycosylated hTREK-1 channel subunits. The data are provided as the mean ± standard error of the mean (SEM). The dashed lines indicate the zero-current levels. The pulse protocols are depicted next to the current traces (* <span class="html-italic">p</span> < 0.05, ** <span class="html-italic">p</span> < 0.01, *** <span class="html-italic">p</span> < 0.001).</p> "> Figure 4
<p><span class="html-italic">N</span>-glycosylation of hTREK-1 currents, expressed in mammalian cells. To determine whether hTREK-1 channel subunits undergo <span class="html-italic">N</span>-glycosylation in mammalian cells, the relevance of the hTREK-1 <span class="html-italic">N</span>-glycosylation sites N110 and N134 was confirmed in HEK-293T cells. (<b>a</b>–<b>c</b>) Protein lysates of HEK-293T cells expressing hTREK-1-1d4 WT or mutant constructs were subjected to anti 1d4-immunoblotting under control conditions, after administration of tunicamycin (TM) or after cleavage of <span class="html-italic">N</span>-linked carbohydrates by the <span class="html-italic">N</span>-glycosidase PNGase F, as indicated by (+) or (−). Changes in carbohydrate modifications are displayed as altered electrophoretic mobility, and immunoblots of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) are provided as loading controls.</p> "> Figure 5
<p><span class="html-italic">N</span>-glycosylation regulates the surface expression of hTREK-1 channels. (<b>a</b>) EGFP-reporter coupled WT hTREK-1 channel subunits or glutamine mutants lacking either one or both <span class="html-italic">N</span>-glycosylation motifs were expressed in HeLa cells. Cell membranes stained with Alexa Fluor 594-labeled wheat germ agglutinin are depicted in red. The fluorescence signals of hTREK-1-eGFP variants are shown in green. The overlays (yellow) demonstrate colocalization of diglycosylated, monoglycosylated and nonglycosylated double-mutant channels with the cellular membrane, and show the preserved surface trafficking of deglycosylated channels. Scale bar: 10 µm. (<b>b</b>) Surface fractions of HEK-293T cells expressing the indicted hTREK-1 <span class="html-italic">N</span>-glycosylation-deficient variants were isolated via surface protein biotinylation, followed by streptavidin precipitation. Immunoblots of the input fractions are displayed on the left, and the mean immunosignals of the surface fractions are given on the right side (<span class="html-italic">n</span> = 3). (<b>c</b>) Ion channel subunit surface fractions (i.e., mean optical densities of the surface blots divided by the input fraction standardized by glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a loading control relative to the WT signal). The data are provided as the mean ± SEM (* <span class="html-italic">p</span> < 0.05).</p> "> Figure 6
<p>There is no evidence for <span class="html-italic">O</span>-glycosylation of hTREK-1 channels. Immunoblots of hTREK-1 are shown for control conditions, after administration of the <span class="html-italic">O</span>-glycosylation inhibitor benzyl 2-acetamido-2-deoxy-α-<span class="html-small-caps">d</span>-galactopyranoside (BenGal) and after incubation of the protein lysates with a mixture of <span class="html-italic">O</span>-glycosidase and neuraminidase (to yield potential <span class="html-italic">O</span>-glycosides accessible to <span class="html-italic">O</span>-glycosidase), as indicated by (+) and (−). However, no mobility shifts could be observed after treatment with BenGal or <span class="html-italic">O</span>-glycosidase, suggesting a lack of significant <span class="html-italic">O</span>-glycosylation of hTREK-1 in HEK-239T cells. The GAPDH signals are provided as loading controls.</p> ">
Abstract
:1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Molecular Biology
4.2. Solutions and Drugs
4.3. Cell Culture and Transfection
4.4. Animal Handling and Oocyte Preparation
4.5. Protein Isolation and Immunoblot Analysis
4.6. Protein Surface Biotinylation
4.7. Two-Electrode Voltage Clamp Electrophysiology
4.8. Immunofluorescence Staining and Fluorescence Microscopy
4.9. Statistical Analysis, Quantification and Data Presentation
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
BenGal | Benzyl 2-acetamido-2-deoxy-α-d-galactopyranoside |
BSA | Bovine serum albumin |
CHAPS | 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate |
DMSO | Dimethylsulfoxide |
EDTA | Ethylene-diamine-tetraacetic acid |
eGFP | enhanced Green Fluorescent Protein |
GAPDH | Glyceraldehyde 3-phosphatedehydrogenase |
HEPES | 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid |
K2P | Two-pore-domain potassium |
PBS | Phosphate-buffered saline |
RMP | Resting membrane potential |
TASK-1 | TWIK-related acid-sensing K+ channel 1 |
TASK-3 | TWIK-related acid-sensing K+ channel 3 |
TASK-5 | TWIK-related acid-sensing K+ channel 5 |
TM | Tunicamycin |
TREK-1 | TWIK-related K+ channel |
TRESK | TWIK-related spinal cord K+ channel |
TWIK | Tandem of P domains in a weak inward rectifying K+ channel |
TEVC | Two-electrode voltage clamp |
TWIK-1 | Tandem of P domains in a weak inward rectifying K+ channel 1 |
WGA | Wheat germ agglutinin |
WT | Wild type |
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Wiedmann, F.; Schlund, D.; Faustino, F.; Kraft, M.; Ratte, A.; Thomas, D.; Katus, H.A.; Schmidt, C. N-Glycosylation of TREK-1/hK2P2.1 Two-Pore-Domain Potassium (K2P) Channels. Int. J. Mol. Sci. 2019, 20, 5193. https://doi.org/10.3390/ijms20205193
Wiedmann F, Schlund D, Faustino F, Kraft M, Ratte A, Thomas D, Katus HA, Schmidt C. N-Glycosylation of TREK-1/hK2P2.1 Two-Pore-Domain Potassium (K2P) Channels. International Journal of Molecular Sciences. 2019; 20(20):5193. https://doi.org/10.3390/ijms20205193
Chicago/Turabian StyleWiedmann, Felix, Daniel Schlund, Francisco Faustino, Manuel Kraft, Antonius Ratte, Dierk Thomas, Hugo A. Katus, and Constanze Schmidt. 2019. "N-Glycosylation of TREK-1/hK2P2.1 Two-Pore-Domain Potassium (K2P) Channels" International Journal of Molecular Sciences 20, no. 20: 5193. https://doi.org/10.3390/ijms20205193