Cardiac and renal inward rectifier potassium channel pharmacology: emerging tools for integrative physiology and therapeutics

doi:10.1016/j.coph.2013.11.002

Review

. 2014 Apr:15:7-15.

doi: 10.1016/j.coph.2013.11.002. Epub 2013 Nov 26.

Cardiac and renal inward rectifier potassium channel pharmacology: emerging tools for integrative physiology and therapeutics

Daniel R Swale¹, Sujay V Kharade¹, Jerod S Denton²

Affiliations

¹ Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
² Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN 37232, United States. Electronic address: Jerod.S.Denton@Vanderbilt.Edu.

PMID: 24721648
PMCID: PMC4097192
DOI: 10.1016/j.coph.2013.11.002

Review

Cardiac and renal inward rectifier potassium channel pharmacology: emerging tools for integrative physiology and therapeutics

Daniel R Swale et al. Curr Opin Pharmacol. 2014 Apr.

. 2014 Apr:15:7-15.

doi: 10.1016/j.coph.2013.11.002. Epub 2013 Nov 26.

Authors

Daniel R Swale¹, Sujay V Kharade¹, Jerod S Denton²

Affiliations

¹ Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
² Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, United States; Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN 37232, United States. Electronic address: Jerod.S.Denton@Vanderbilt.Edu.

PMID: 24721648
PMCID: PMC4097192
DOI: 10.1016/j.coph.2013.11.002

Abstract

Inward rectifier potassium (Kir) channels play fundamental roles in cardiac and renal function and may represent unexploited drug targets for cardiovascular diseases. However, the limited pharmacology of Kir channels has slowed progress toward exploring their integrative physiology and therapeutic potential. Here, we review recent progress toward developing the small-molecule pharmacology for Kir2.x, Kir4.1, and Kir7.1 and discuss common mechanistic themes that may help guide future Kir channel-directed drug discovery efforts.

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Figures

**Figure 1. Putative small-molecule binding sites in a model Kir channel**
A) Side B) Top and C) Bottom view of chicken Kir2.2 crystal structure with equivalent residues implicated in small-molecule binding highlighted with sphere. Channel-specific residues are indicated in the legend. See text and Table 1 for details.

See this image and copyright information in PMC

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References

1. Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y. Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev. 2010;90(1):291–366. - PubMed
1. Tao X, Avalos JL, Chen J, MacKinnon R. Crystal structure of the eukaryotic strong inward-rectifier K+ channel Kir2.2 at 3.1 A resolution. Science. 2009;326(5960):1668–1674. - PMC - PubMed
1. Lu Z, MacKinnon R. Electrostatic tuning of Mg2+ affinity in an inward-rectifier K+ channel. Nature. 1994;371(6494):243–246. - PubMed
1. Ficker E, Taglialatela M, Wible BA, Henley CM, Brown AM. Spermine and spermidine as gating molecules for inward rectifier K+ channels. Science. 1994;266(5187):1068–1072. - PubMed
1. Wible BA, Taglialatela M, Ficker E, Brown AM. Gating of inwardly rectifying K+ channels 1localized to a single negatively charged residue. Nature. 1994;371(6494):246–249. - PubMed

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[1] Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y. Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev. 2010;90(1):291–366. - PubMed

[2] Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y. Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev. 2010;90(1):291–366. - PubMed

[3] Tao X, Avalos JL, Chen J, MacKinnon R. Crystal structure of the eukaryotic strong inward-rectifier K+ channel Kir2.2 at 3.1 A resolution. Science. 2009;326(5960):1668–1674. - PMC - PubMed

[4] Tao X, Avalos JL, Chen J, MacKinnon R. Crystal structure of the eukaryotic strong inward-rectifier K+ channel Kir2.2 at 3.1 A resolution. Science. 2009;326(5960):1668–1674. - PMC - PubMed

[5] Lu Z, MacKinnon R. Electrostatic tuning of Mg2+ affinity in an inward-rectifier K+ channel. Nature. 1994;371(6494):243–246. - PubMed

[6] Lu Z, MacKinnon R. Electrostatic tuning of Mg2+ affinity in an inward-rectifier K+ channel. Nature. 1994;371(6494):243–246. - PubMed

[7] Ficker E, Taglialatela M, Wible BA, Henley CM, Brown AM. Spermine and spermidine as gating molecules for inward rectifier K+ channels. Science. 1994;266(5187):1068–1072. - PubMed

[8] Ficker E, Taglialatela M, Wible BA, Henley CM, Brown AM. Spermine and spermidine as gating molecules for inward rectifier K+ channels. Science. 1994;266(5187):1068–1072. - PubMed

[9] Wible BA, Taglialatela M, Ficker E, Brown AM. Gating of inwardly rectifying K+ channels 1localized to a single negatively charged residue. Nature. 1994;371(6494):246–249. - PubMed

[10] Wible BA, Taglialatela M, Ficker E, Brown AM. Gating of inwardly rectifying K+ channels 1localized to a single negatively charged residue. Nature. 1994;371(6494):246–249. - PubMed

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Cardiac and renal inward rectifier potassium channel pharmacology: emerging tools for integrative physiology and therapeutics

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Cardiac and renal inward rectifier potassium channel pharmacology: emerging tools for integrative physiology and therapeutics

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