Towards the Development of AgoKirs: New Pharmacological Activators to Study K<sub>ir</sub>2.x Channel and Target Cardiac Disease
Inward rectifier potassium ion channels (I<sub>K1</sub>-channels) of the K<sub>ir</sub>2.x family are responsible for maintaining a stable negative resting membrane potential in excitable cells, but also play a role in processes of non-excitable tissues, such as bone developm...
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| Format: | Article |
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MDPI AG
2020-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/16/5746 |
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| author | Laura van der Schoor Emma J. van Hattum Sophie M. de Wilde Netanja I. Harlianto Aart-Jan van Weert Meye Bloothooft Marcel A. G. van der Heyden |
| author_facet | Laura van der Schoor Emma J. van Hattum Sophie M. de Wilde Netanja I. Harlianto Aart-Jan van Weert Meye Bloothooft Marcel A. G. van der Heyden |
| author_sort | Laura van der Schoor |
| collection | DOAJ |
| description | Inward rectifier potassium ion channels (I<sub>K1</sub>-channels) of the K<sub>ir</sub>2.x family are responsible for maintaining a stable negative resting membrane potential in excitable cells, but also play a role in processes of non-excitable tissues, such as bone development. I<sub>K1</sub>-channel loss-of-function, either congenital or acquired, has been associated with cardiac disease. Currently, basic research and specific treatment are hindered by the absence of specific and efficient K<sub>ir</sub>2.x channel activators. However, twelve different compounds, including approved drugs, show off-target I<sub>K1</sub> activation. Therefore, these compounds contain valuable information towards the development of agonists of K<sub>ir</sub> channels, AgoKirs. We reviewed the mechanism of I<sub>K1</sub> channel activation of these compounds, which can be classified as direct or indirect activators. Subsequently, we examined the most viable starting points for rationalized drug development and possible safety concerns with emphasis on cardiac and skeletal muscle adverse effects of AgoKirs. Finally, the potential value of AgoKirs is discussed in view of the current clinical applications of potentiators and activators in cystic fibrosis therapy. |
| first_indexed | 2024-03-10T17:40:09Z |
| format | Article |
| id | doaj.art-bd7fef4d775241e28ee91b6e5c18aa20 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T17:40:09Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-bd7fef4d775241e28ee91b6e5c18aa202023-11-20T09:44:44ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-08-012116574610.3390/ijms21165746Towards the Development of AgoKirs: New Pharmacological Activators to Study K<sub>ir</sub>2.x Channel and Target Cardiac DiseaseLaura van der Schoor0Emma J. van Hattum1Sophie M. de Wilde2Netanja I. Harlianto3Aart-Jan van Weert4Meye Bloothooft5Marcel A. G. van der Heyden6Honours Program CRU+ Bachelor, University Medical Center Utrecht, Heidelberglaan 100, 3584 CM Utrecht, The NetherlandsHonours Program CRU+ Bachelor, University Medical Center Utrecht, Heidelberglaan 100, 3584 CM Utrecht, The NetherlandsHonours Program CRU+ Bachelor, University Medical Center Utrecht, Heidelberglaan 100, 3584 CM Utrecht, The NetherlandsHonours Program CRU+ Bachelor, University Medical Center Utrecht, Heidelberglaan 100, 3584 CM Utrecht, The NetherlandsHonours Program CRU+ Bachelor, University Medical Center Utrecht, Heidelberglaan 100, 3584 CM Utrecht, The NetherlandsDepartment of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, 3584 CM Utrecht, The NetherlandsDepartment of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, 3584 CM Utrecht, The NetherlandsInward rectifier potassium ion channels (I<sub>K1</sub>-channels) of the K<sub>ir</sub>2.x family are responsible for maintaining a stable negative resting membrane potential in excitable cells, but also play a role in processes of non-excitable tissues, such as bone development. I<sub>K1</sub>-channel loss-of-function, either congenital or acquired, has been associated with cardiac disease. Currently, basic research and specific treatment are hindered by the absence of specific and efficient K<sub>ir</sub>2.x channel activators. However, twelve different compounds, including approved drugs, show off-target I<sub>K1</sub> activation. Therefore, these compounds contain valuable information towards the development of agonists of K<sub>ir</sub> channels, AgoKirs. We reviewed the mechanism of I<sub>K1</sub> channel activation of these compounds, which can be classified as direct or indirect activators. Subsequently, we examined the most viable starting points for rationalized drug development and possible safety concerns with emphasis on cardiac and skeletal muscle adverse effects of AgoKirs. Finally, the potential value of AgoKirs is discussed in view of the current clinical applications of potentiators and activators in cystic fibrosis therapy.https://www.mdpi.com/1422-0067/21/16/5746inward rectifier channelK<sub>ir</sub>2agonistI<sub>K1</sub>Andersen syndromeheart failure |
| spellingShingle | Laura van der Schoor Emma J. van Hattum Sophie M. de Wilde Netanja I. Harlianto Aart-Jan van Weert Meye Bloothooft Marcel A. G. van der Heyden Towards the Development of AgoKirs: New Pharmacological Activators to Study K<sub>ir</sub>2.x Channel and Target Cardiac Disease International Journal of Molecular Sciences inward rectifier channel K<sub>ir</sub>2 agonist I<sub>K1</sub> Andersen syndrome heart failure |
| title | Towards the Development of AgoKirs: New Pharmacological Activators to Study K<sub>ir</sub>2.x Channel and Target Cardiac Disease |
| title_full | Towards the Development of AgoKirs: New Pharmacological Activators to Study K<sub>ir</sub>2.x Channel and Target Cardiac Disease |
| title_fullStr | Towards the Development of AgoKirs: New Pharmacological Activators to Study K<sub>ir</sub>2.x Channel and Target Cardiac Disease |
| title_full_unstemmed | Towards the Development of AgoKirs: New Pharmacological Activators to Study K<sub>ir</sub>2.x Channel and Target Cardiac Disease |
| title_short | Towards the Development of AgoKirs: New Pharmacological Activators to Study K<sub>ir</sub>2.x Channel and Target Cardiac Disease |
| title_sort | towards the development of agokirs new pharmacological activators to study k sub ir sub 2 x channel and target cardiac disease |
| topic | inward rectifier channel K<sub>ir</sub>2 agonist I<sub>K1</sub> Andersen syndrome heart failure |
| url | https://www.mdpi.com/1422-0067/21/16/5746 |
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