1: Curr Pharm Des. 2006;12(18):2271-83.


The cardiac hERG/IKr potassium channel as pharmacological target: structure, function, regulation, and clinical applications.

Thomas D, Karle CA, Kiehn J.

Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.

Human ether-a-go-go-related gene (hERG) potassium channels conduct the rapid component of the delayed rectifier potassium current, IKr, which is crucial for repolarization of cardiac action potentials. Moderate hERG blockade may produce a beneficial class III antiarrhythmic effect. In contrast, a reduction in hERG currents due to either genetic defects or adverse drug effects can lead to hereditary or acquired long QT syndromes characterized by action potential prolongation, lengthening of the QT interval on the surface ECG, and an increased risk for "torsade de pointes" arrhythmias and sudden death. This undesirable side effect of non-antiarrhythmic compounds has prompted the withdrawal of several blockbuster drugs from the market. Studies on mechanisms of hERG channel inhibition provide significant insights into the molecular factors that determine state-, voltage-, and use-dependency of hERG current block. In addition, crucial properties of the high-affinity drug binding site in hERG and its interaction with drug molecules have been identified, providing the basis for more refined approaches in drug design, safety pharmacology and in silico modeling. Recently, mutations in hERG have been shown to cause current increase and hereditary short QT syndrome with a high risk for life-threatening arrhythmias. Finally, the discovery of adrenergic mechanisms of hERG channel regulation as well as the development of strategies to enhance hERG currents and to modify intracellular hERG protein processing may provide novel antiarrhythmic options in repolarization disorders. In conclusion, the increasing understanding of hERG channel function and molecular mechanisms of hERG current regulation could improve prevention and treatment of hERG-associated cardiac repolarization disorders.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 16787254 [PubMed - indexed for MEDLINE]

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2: Curr Opin Struct Biol. 2000 Aug;10(4):456-61.


Potassium channel structure: domain by domain.

Biggin PC, Roosild T, Choe S.

Structural Biology Laboratory, The Salk Institute, La Jolla, CA 92037, USA.

Since the determination of the structure of a bacterial potassium channel, the ion channel community has managed to gain momentum in the quest for a complete picture. The information is coming at a steady flow, on a domain by domain basis. Recent discoveries are starting to reveal clues to the complex manner in which potassium channels show enormous diversity of function and also to their methods of regulation. Currently, the structures of four domains are known, with the most recent addition being the Kvbeta structure. As efforts continue in the study of the transmembrane domains, especially the voltage-sensing apparatus, there has been a new realization with respect to the identification and role of the cytoplasmic domains in protein-protein interactions in particular. An additional discovery, considerably aided by recent genomic analysis, is that potassium channels comprising subunits with two pore regions and four transmembrane helices combined in a dimeric fashion are abundant and are probable targets for local anesthetics.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 10981635 [PubMed - indexed for MEDLINE]

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3: Novartis Found Symp. 1999;225:23-32; discussion 33-7.


X-ray crystallographic structures of gramicidin and their relation to the Streptomyces lividans potassium channel structure.

Wallace BA.

Department of Crystallography, Birkbeck College, University of London, UK.

Gramicidin has been used extensively as a model system for structure/function studies of ion channels. Long before crystals of other ion channel proteins were produced, crystals of gramicidin had been prepared, even though it was many years before the first forms of those crystals were solved. There now exist a large number of crystal structures of both uncomplexed and ion-complexed forms of gramicidin crystallized from organic solvents. In all these crystals, the molecules are double helices, although they differ in helical pitch, handedness and side chain orientations, depending on the conditions used for crystallization. Since many of these structures have been discussed in detail in a recent review (Wallace 1998), this chapter concentrates on recently reported structures and how they relate to previously described X-ray and NMR structures. It also discusses how the crystal structure of a K+ complex of gramicidin relates to the recently solved structure of a K+ complex of the potassium channel from Streptomyces lividans and argues that this demonstrates that gramicidin is indeed a good model structure for biological ion channels, despite the presence of D-amino acids in its sequence.

Publication Types:
Comparative Study
Review

PMID: 10472045 [PubMed - indexed for MEDLINE]

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4: Biochimie. 1998 Feb;80(2):151-4.


Synthetic peptides as tools to investigate the structure and pharmacology of potassium channel-acting short-chain scorpion toxins.

Lecomte C, Sabatier JM, Van Rietschoten J, Rochat H.

Laboratoire de Biochimie, Ingéniérie des Protéines, CNRS UMR 6560, IFR Jean Roche, Faculté de Médecine Nord, Marseille, France.

In the last decade, numerous polypeptide toxins acting on ion channels have been isolated and characterized from diverse scorpion venoms. These toxins are useful pharmacological probes to study ion-specific channel proteins because they interact selectively with these channels and modulate their activities. Since low amounts of natural toxins can be isolated from scorpion venoms, the chemical synthesis approach is extremely useful to produce larger quantities of toxins and toxin analogs. This report is a succinct overview of the possibilities offered by the chemical synthesis to investigate pharmacological and structural properties of these compounds.

Publication Types:
Review

PMID: 9587672 [PubMed - indexed for MEDLINE]

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5: Prog Med Chem. 1994;31:411-46.


Potassium channel activators: pharmacological methods, models, and structure-activity relationships.

Evans JM, Taylor SG.

SmithKline Beecham Pharmaceuticals, Pinnacles, Harlow, Essex, U.K.

Publication Types:
Review

PMID: 8029480 [PubMed - indexed for MEDLINE]

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6: Neurochem Res. 1992 Sep;17(9):869-76.


Structure and regulation of the MinK potassium channel.

Blumenthal EM, Kaczmarek LK.

Interdepartmental Neuroscience Program, Yale University Medical School, New Haven, CT 06510.

MinK is a novel protein which induces an extremely slowly activating potassium channel when expressed in Xenopus oocytes. We discuss the properties and regulation of the current and localization and possible physiological roles of the MinK protein.

Publication Types:
Review

PMID: 1407274 [PubMed - indexed for MEDLINE]

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7: Annu Rev Biophys Biophys Chem. 1987;16:227-46.


Permeation in potassium channels: implications for channel structure.

Yellen G.

The SR K+ channel is a single-ion channel with a tunnel that is not very selective, while the DR and CaK channels are both more selective, multi-ion channels. The permeation mechanisms of the three channels are probably most systematically distinguished by the length of their tunnels; the SR has the shortest and the DR the longest. Although different in their mechanisms of activation, the DR and CaK channels have very similar permeation characteristics, down to the details of selectivity and blockade. The longer tunnel and reduced conductance (perhaps a result of the extra tunnel length) of the DR K+ channel are the main differences. The selectivity of the rate-limiting barriers and the binding sites within the channels, however, are strikingly similar. A successful potassium channel must satisfy two criteria: It must let potassium ions through and not much else, and it must let many potassium ions through. To be selective the channel must have a narrow selectivity filter, so that an ion must shed some of its waters of hydration to pass through. Sodium ions are excluded because they are more reluctant to lose their water, and they are not adequately compensated for this loss by interaction with the selectivity filter. To carry a large current the narrow region must be short, with wide antechambers to reduce the diffusional access resistance (48). Energetically, the channel must strike a balance. There must be enough binding energy to compensate the ions for their lost hydration energy, so that the energy barrier to permeation is small. If the channel binds the ion too tightly, however, the ion will not be able to exit, and the current will be small. Some of the shared properties of different potassium channels are probably consequences of these requirements; others may be incidental to function, suggesting a common origin. Barium ions have almost exactly the same radius as potassium ions but twice the charge, so it is perhaps not surprising that barium can block any potassium channel by binding where potassium does, but too tightly. It seems more surprising that blockade by TEA+ and other quaternary ammonium ions is also well conserved. All three of the potassium channels considered here have a mouth that binds QA ions and that has a nearby hydrophobic pocket; the frog DR and the CaK channels also have a TEA+-specific site on the opposite side. The QA site might not be an obligatory feature of potassium channels, but rather a conserved evolutionary vestige.(ABSTRACT TRUNCATED AT 400 WORDS)

Publication Types:
Review

PMID: 2439096 [PubMed - indexed for MEDLINE]