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Gap19, a Cx43 hemichannel inhibitor, acts as a gating modifier that decreases main state opening while increasing substate gating

Alessio Lissoni (UGent) , Nan Wang (UGent) , Timur Nezlobinskii (UGent) , Maarten De Smet (UGent) , Alexander Panfilov (UGent) , Nele Vandersickel (UGent) , Luc Leybaert (UGent) and Katja Witschas (UGent)
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Organization
Abstract
Cx43 hemichannels (HCs) are electrically and chemically gated transmembrane pores with low open probability and multiple conductance states, which makes kinetic studies of channel gating in large datasets challenging. Here, we developed open access software, named HemiGUI, to analyze HC gating transitions and investigated voltage-induced HC opening based on up to ≈4000 events recorded in HeLa-Cx43-overexpressing cells. We performed a detailed characterization of Cx43 HC gating profiles and specifically focused on the role of the C-terminal tail (CT) domain by recording the impact of adding an EGFP tag to the Cx43 CT end (Cx43-EGFP) or by supplying the Cx43 HC-inhibiting peptide Gap19 that interferes with CT interaction with the cytoplasmic loop (CL). We found that Gap19 not only decreased HC opening activity to the open state (≈217 pS) but also increased the propensity of subconductance (≈80 pS) transitions that additionally became slower as compared to the control. The work demonstrates that large sample transition analysis allows detailed investigations on Cx43 HC gating and shows that Gap19 acts as a HC gating modifier by interacting with the CT that forms a crucial gating element.
Keywords
ion channel gating, graphic user interface, automated analysis, transition analysis, Computer Science Applications, JUNCTION CHANNELS, CONNEXIN43, VOLTAGE, REVERSAL, PERMEATION, TERMINUS, POLARITY

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MLA
Lissoni, Alessio, et al. “Gap19, a Cx43 Hemichannel Inhibitor, Acts as a Gating Modifier That Decreases Main State Opening While Increasing Substate Gating.” INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 21, no. 19, 2020, doi:10.3390/ijms21197340.
APA
Lissoni, A., Wang, N., Nezlobinskii, T., De Smet, M., Panfilov, A., Vandersickel, N., … Witschas, K. (2020). Gap19, a Cx43 hemichannel inhibitor, acts as a gating modifier that decreases main state opening while increasing substate gating. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 21(19). https://doi.org/10.3390/ijms21197340
Chicago author-date
Lissoni, Alessio, Nan Wang, Timur Nezlobinskii, Maarten De Smet, Alexander Panfilov, Nele Vandersickel, Luc Leybaert, and Katja Witschas. 2020. “Gap19, a Cx43 Hemichannel Inhibitor, Acts as a Gating Modifier That Decreases Main State Opening While Increasing Substate Gating.” INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 21 (19). https://doi.org/10.3390/ijms21197340.
Chicago author-date (all authors)
Lissoni, Alessio, Nan Wang, Timur Nezlobinskii, Maarten De Smet, Alexander Panfilov, Nele Vandersickel, Luc Leybaert, and Katja Witschas. 2020. “Gap19, a Cx43 Hemichannel Inhibitor, Acts as a Gating Modifier That Decreases Main State Opening While Increasing Substate Gating.” INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 21 (19). doi:10.3390/ijms21197340.
Vancouver
1.
Lissoni A, Wang N, Nezlobinskii T, De Smet M, Panfilov A, Vandersickel N, et al. Gap19, a Cx43 hemichannel inhibitor, acts as a gating modifier that decreases main state opening while increasing substate gating. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. 2020;21(19).
IEEE
[1]
A. Lissoni et al., “Gap19, a Cx43 hemichannel inhibitor, acts as a gating modifier that decreases main state opening while increasing substate gating,” INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 21, no. 19, 2020.
@article{8676716,
  abstract     = {Cx43 hemichannels (HCs) are electrically and chemically gated transmembrane pores with low open probability and multiple conductance states, which makes kinetic studies of channel gating in large datasets challenging. Here, we developed open access software, named HemiGUI, to analyze HC gating transitions and investigated voltage-induced HC opening based on up to ≈4000 events recorded in HeLa-Cx43-overexpressing cells. We performed a detailed characterization of Cx43 HC gating profiles and specifically focused on the role of the C-terminal tail (CT) domain by recording the impact of adding an EGFP tag to the Cx43 CT end (Cx43-EGFP) or by supplying the Cx43 HC-inhibiting peptide Gap19 that interferes with CT interaction with the cytoplasmic loop (CL). We found that Gap19 not only decreased HC opening activity to the open state (≈217 pS) but also increased the propensity of subconductance (≈80 pS) transitions that additionally became slower as compared to the control. The work demonstrates that large sample transition analysis allows detailed investigations on Cx43 HC gating and shows that Gap19 acts as a HC gating modifier by interacting with the CT that forms a crucial gating element.},
  articleno    = {7340},
  author       = {Lissoni, Alessio and Wang, Nan and Nezlobinskii, Timur and De Smet, Maarten and Panfilov, Alexander and Vandersickel, Nele and Leybaert, Luc and Witschas, Katja},
  issn         = {1422-0067},
  journal      = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES},
  keywords     = {ion channel gating,graphic user interface,automated analysis,transition analysis,Computer Science Applications,JUNCTION CHANNELS,CONNEXIN43,VOLTAGE,REVERSAL,PERMEATION,TERMINUS,POLARITY},
  language     = {eng},
  number       = {19},
  pages        = {15},
  title        = {Gap19, a Cx43 hemichannel inhibitor, acts as a gating modifier that decreases main state opening while increasing substate gating},
  url          = {http://dx.doi.org/10.3390/ijms21197340},
  volume       = {21},
  year         = {2020},
}

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