Abstract
For the past two decades several scholarly reviews have appeared on the inwardly rectifying potassium (Kir) channels. We would like to highlight two efforts in particular, which have provided comprehensive reviews of the literature up to 2010 (Hibino et al., Physiol Rev 90(1):291–366, 2010; Stanfield et al., Rev Physiol Biochem Pharmacol 145:47–179, 2002). In the past decade, great insights into the 3-D atomic resolution structures of Kir channels have begun to provide the molecular basis for their functional properties. More recently, computational studies are beginning to close the time domain gap between in silico dynamic and patch-clamp functional studies. The pharmacology of these channels has also been expanding and the dynamic structural studies provide hope that we are heading toward successful structure-based drug design for this family of K+ channels. In the present review we focus on placing the physiology and pharmacology of this K+ channel family in the context of atomic resolution structures and in providing a glimpse of the promising future of therapeutic opportunities.
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Acknowledgements
We dedicate this review to Dr. Yoshihisa Kurachi who by devoting his career to Kir channel structure, function, and pharmacology has inspired many of us to follow his example. We are grateful to Professor Leigh Plant for reading this review and providing us with critical feedback. We thank the members of the Logothetis and Plant groups for pursuing and freely sharing their mechanistic Kir channel results. Last but not least, we thank the National Institutes of Health (NIH) in the United States of America (USA) for funding our research and thus allowing us to continue working in this exciting field (supported by NIH R01-HL059949-23 to D.E.L.)
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Appendix
Appendix
Inwardly rectifying potassium channel family alignment. The current human 16 members of the Kir family were aligned using the Clustal Omega multiple sequence alignment program, which uses seeded guide trees and HMM profile–profile techniques to generate the alignments for all Kir members. Fully conserved resides are denoted with an “*”, residues with strongly similar properties are denoted with a “:”, and residues with weakly similar properties are donated with a “.”. The important structural and gating features are highlighted and labeled (Madiera et al. 2019)
Inwardly rectifying potassium channel family similarity and identity. The 16 members of the Kir family were analyzed for percent similarity and percent identity using the Sequence Identity And Similarity (SIAS) tool which uses a pairwise analyses utilizing several methods. Amino acid similarity and sequence length is used to calculate the values (% = 100*(identical| similar residues/sequence length)). Parameters were set to the standard settings relative to amino acid similarities. Sequences were input from the Clustal Omega alignment. The values are listed as percent similarity/% identity
Chemical structures of drugs targeting Kir channels
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Cui, M., Cantwell, L., Zorn, A., Logothetis, D.E. (2021). Kir Channel Molecular Physiology, Pharmacology, and Therapeutic Implications. In: Gamper, N., Wang, K. (eds) Pharmacology of Potassium Channels. Handbook of Experimental Pharmacology, vol 267. Springer, Cham. https://doi.org/10.1007/164_2021_501
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DOI: https://doi.org/10.1007/164_2021_501
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