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Review

Towards the Development of AgoKirs: New Pharmacological Activators to Study Kir2.x Channel and Target Cardiac Disease

1
Honours Program CRU+ Bachelor, University Medical Center Utrecht, Heidelberglaan 100, 3584 CM Utrecht, The Netherlands
2
Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, 3584 CM Utrecht, The Netherlands
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(16), 5746; https://doi.org/10.3390/ijms21165746
Received: 10 July 2020 / Revised: 5 August 2020 / Accepted: 6 August 2020 / Published: 11 August 2020
(This article belongs to the Special Issue New Insights into Cardiac Ion Channel Regulation)
Inward rectifier potassium ion channels (IK1-channels) of the Kir2.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. IK1-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 Kir2.x channel activators. However, twelve different compounds, including approved drugs, show off-target IK1 activation. Therefore, these compounds contain valuable information towards the development of agonists of Kir channels, AgoKirs. We reviewed the mechanism of IK1 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. View Full-Text
Keywords: inward rectifier channel; Kir2; agonist; IK1; Andersen syndrome; heart failure inward rectifier channel; Kir2; agonist; IK1; Andersen syndrome; heart failure
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MDPI and ACS Style

van der Schoor, L.; van Hattum, E.J.; de Wilde, S.M.; Harlianto, N.I.; van Weert, A.-J.; Bloothooft, M.; van der Heyden, M.A.G. Towards the Development of AgoKirs: New Pharmacological Activators to Study Kir2.x Channel and Target Cardiac Disease. Int. J. Mol. Sci. 2020, 21, 5746. https://doi.org/10.3390/ijms21165746

AMA Style

van der Schoor L, van Hattum EJ, de Wilde SM, Harlianto NI, van Weert A-J, Bloothooft M, van der Heyden MAG. Towards the Development of AgoKirs: New Pharmacological Activators to Study Kir2.x Channel and Target Cardiac Disease. International Journal of Molecular Sciences. 2020; 21(16):5746. https://doi.org/10.3390/ijms21165746

Chicago/Turabian Style

van der Schoor, Laura, Emma J. van Hattum, Sophie M. de Wilde, Netanja I. Harlianto, Aart-Jan van Weert, Meye Bloothooft, and Marcel A.G. van der Heyden 2020. "Towards the Development of AgoKirs: New Pharmacological Activators to Study Kir2.x Channel and Target Cardiac Disease" International Journal of Molecular Sciences 21, no. 16: 5746. https://doi.org/10.3390/ijms21165746

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