5-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human H<sub>V</sub>1 Channel
5-chloro-2-guanidinobenzimidazole (ClGBI), a small-molecule guanidine derivative, is a known effective inhibitor of the voltage-gated proton (H<sup>+</sup>) channel (H<sub>V</sub>1, <i>K<sub>d</sub></i> ≈ 26 μM) and is widely used both in ion channel r...
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| Format: | Article |
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MDPI AG
2023-04-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/5/656 |
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| author | Tibor G. Szanto Adam Feher Eva Korpos Adrienn Gyöngyösi Judit Kállai Beáta Mészáros Krisztian Ovari Árpád Lányi Gyorgy Panyi Zoltan Varga |
| author_facet | Tibor G. Szanto Adam Feher Eva Korpos Adrienn Gyöngyösi Judit Kállai Beáta Mészáros Krisztian Ovari Árpád Lányi Gyorgy Panyi Zoltan Varga |
| author_sort | Tibor G. Szanto |
| collection | DOAJ |
| description | 5-chloro-2-guanidinobenzimidazole (ClGBI), a small-molecule guanidine derivative, is a known effective inhibitor of the voltage-gated proton (H<sup>+</sup>) channel (H<sub>V</sub>1, <i>K<sub>d</sub></i> ≈ 26 μM) and is widely used both in ion channel research and functional biological assays. However, a comprehensive study of its ion channel selectivity determined by electrophysiological methods has not been published yet. The lack of selectivity may lead to incorrect conclusions regarding the role of hHv1 in physiological or pathophysiological responses in vitro and in vivo. We have found that ClGBI inhibits the proliferation of lymphocytes, which absolutely requires the functioning of the K<sub>V</sub>1.3 channel. We, therefore, tested ClGBI directly on hK<sub>V</sub>1.3 using a whole-cell patch clamp and found an inhibitory effect similar in magnitude to that seen on hH<sub>V</sub>1 (<i>K<sub>d</sub></i> ≈ 72 μM). We then further investigated ClGBI selectivity on the hK<sub>V</sub>1.1, hK<sub>V</sub>1.4-IR, hK<sub>V</sub>1.5, hK<sub>V</sub>10.1, hK<sub>V</sub>11.1, hK<sub>Ca</sub>3.1, hNa<sub>V</sub>1.4, and hNa<sub>V</sub>1.5 channels. Our results show that, besides H<sub>V</sub>1 and K<sub>V</sub>1.3, all other off-target channels were inhibited by ClGBI, with <i>K<sub>d</sub></i> values ranging from 12 to 894 μM. Based on our comprehensive data, ClGBI has to be considered a non-selective hH<sub>V</sub>1 inhibitor; thus, experiments aiming at elucidating the significance of these channels in physiological responses have to be carefully evaluated. |
| first_indexed | 2024-03-11T03:25:55Z |
| format | Article |
| id | doaj.art-e7f674d9917e473ca32a50d14f6f19ab |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T03:25:55Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-e7f674d9917e473ca32a50d14f6f19ab2023-11-18T02:48:05ZengMDPI AGPharmaceuticals1424-82472023-04-0116565610.3390/ph160506565-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human H<sub>V</sub>1 ChannelTibor G. Szanto0Adam Feher1Eva Korpos2Adrienn Gyöngyösi3Judit Kállai4Beáta Mészáros5Krisztian Ovari6Árpád Lányi7Gyorgy Panyi8Zoltan Varga9Department of Biophysics & Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Biophysics & Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Biophysics & Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Immunology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryELKH-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Biophysics & Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Biophysics & Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Immunology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Biophysics & Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, HungaryDepartment of Biophysics & Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary5-chloro-2-guanidinobenzimidazole (ClGBI), a small-molecule guanidine derivative, is a known effective inhibitor of the voltage-gated proton (H<sup>+</sup>) channel (H<sub>V</sub>1, <i>K<sub>d</sub></i> ≈ 26 μM) and is widely used both in ion channel research and functional biological assays. However, a comprehensive study of its ion channel selectivity determined by electrophysiological methods has not been published yet. The lack of selectivity may lead to incorrect conclusions regarding the role of hHv1 in physiological or pathophysiological responses in vitro and in vivo. We have found that ClGBI inhibits the proliferation of lymphocytes, which absolutely requires the functioning of the K<sub>V</sub>1.3 channel. We, therefore, tested ClGBI directly on hK<sub>V</sub>1.3 using a whole-cell patch clamp and found an inhibitory effect similar in magnitude to that seen on hH<sub>V</sub>1 (<i>K<sub>d</sub></i> ≈ 72 μM). We then further investigated ClGBI selectivity on the hK<sub>V</sub>1.1, hK<sub>V</sub>1.4-IR, hK<sub>V</sub>1.5, hK<sub>V</sub>10.1, hK<sub>V</sub>11.1, hK<sub>Ca</sub>3.1, hNa<sub>V</sub>1.4, and hNa<sub>V</sub>1.5 channels. Our results show that, besides H<sub>V</sub>1 and K<sub>V</sub>1.3, all other off-target channels were inhibited by ClGBI, with <i>K<sub>d</sub></i> values ranging from 12 to 894 μM. Based on our comprehensive data, ClGBI has to be considered a non-selective hH<sub>V</sub>1 inhibitor; thus, experiments aiming at elucidating the significance of these channels in physiological responses have to be carefully evaluated.https://www.mdpi.com/1424-8247/16/5/656ClGBIproton channelvoltage-gated ion channelsblocking kineticsselectivity screening |
| spellingShingle | Tibor G. Szanto Adam Feher Eva Korpos Adrienn Gyöngyösi Judit Kállai Beáta Mészáros Krisztian Ovari Árpád Lányi Gyorgy Panyi Zoltan Varga 5-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human H<sub>V</sub>1 Channel Pharmaceuticals ClGBI proton channel voltage-gated ion channels blocking kinetics selectivity screening |
| title | 5-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human H<sub>V</sub>1 Channel |
| title_full | 5-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human H<sub>V</sub>1 Channel |
| title_fullStr | 5-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human H<sub>V</sub>1 Channel |
| title_full_unstemmed | 5-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human H<sub>V</sub>1 Channel |
| title_short | 5-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human H<sub>V</sub>1 Channel |
| title_sort | 5 chloro 2 guanidinobenzimidazole clgbi is a non selective inhibitor of the human h sub v sub 1 channel |
| topic | ClGBI proton channel voltage-gated ion channels blocking kinetics selectivity screening |
| url | https://www.mdpi.com/1424-8247/16/5/656 |
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