Kv11.1 (ERG1) K<sup>+</sup>Channels Localize in Cholesterol and Sphingolipid Enriched Membranes and Are Modulated by Membrane Cholesterol

Balijepalli, Ravi C.; Delisle, Brian P.; Balijepalli, Sadguna Y.; Foell, Jason D.; Slind, Jessica K.; Kamp, Timothy J.; January, Craig T.

doi:10.4161/chan.4946

Cited by 55 publications

(49 citation statements)

References 57 publications

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“…To detect the contractile protein actin, cardiomyocytes were incubated with a monoclonal mouse anti-sarcomeric actin antibody (1:1,000, Sigma-Aldrich) that was counterstained with Alexa 405 (Molecular Probes, Eugene, OR). To detect hERG protein, cardiomyocytes were incubated with antihERG antibody as previously described (6). The immunofluorescence was viewed with a Nikon fluorescence microscope (7).…”

Section: Methodsmentioning

confidence: 99%

Properties of WT and mutant hERG K⁺ channels expressed in neonatal mouse cardiomyocytes

Lin

Holzem

Anson

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Mutations in humanether-a-go-go-related gene 1 (hERG) are linked to long QT syndrome type 2 (LQT2). hERG encodes the pore-forming ␣-subunits that coassemble to form rapidly activating delayed rectifier K ϩ current in the heart. LQT2-linked missense mutations have been extensively studied in noncardiac heterologous expression systems, where biogenic (protein trafficking) and biophysical (gating and permeation) abnormalities have been postulated to underlie the loss-of-function phenotype associated with LQT2 channels. Little is known about the properties of LQT2-linked hERG channel proteins in native cardiomyocyte systems. In this study, we expressed wild-type (WT) hERG and three LQT2-linked mutations in neonatal mouse cardiomyocytes and studied their electrophysiological and biochemical properties. Compared with WT hERG channels, the LQT2 missense mutations G601S and N470D hERG exhibited altered protein trafficking and underwent pharmacological correction, and N470D hERG channels gated at more negative voltages. The ⌬Y475 hERG deletion mutation trafficked similar to WT hERG channels, gated at more negative voltages, and had rapid deactivation kinetics, and these properties were confirmed in both neonatal mouse cardiomyocyte and human embryonic kidney (HEK)-293 cell expression systems. Differences between the cardiomyocytes and HEK-293 cell expression systems were that hERG current densities were reduced 10-fold and deactivation kinetics were accelerated 1.5-to 2-fold in neonatal mouse cardiomyocytes. An important finding of this work is that pharmacological correction of trafficking-deficient LQT2 mutations, as a potential innovative approach to therapy, is possible in native cardiac tissue.

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Section: Methodsmentioning

confidence: 99%

Properties of WT and mutant hERG K⁺ channels expressed in neonatal mouse cardiomyocytes

Lin

Holzem

Anson

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…Obesity is associated with increased circulating levels of cholesterol and leptin 34 . Cholesterol levels are higher in caveoli 35 , the location of hERG a-and b-subunit insertions 36 . Direct interaction may occur between membrane lipids and amino acids in membrane-traversing domains of ion channel proteins 37 , and hERG channel kinetics are sensitive to the cholesterol content of the plasma membrane 36 .…”

Section: Discussionmentioning

confidence: 99%

“…Cholesterol levels are higher in caveoli 35 , the location of hERG a-and b-subunit insertions 36 . Direct interaction may occur between membrane lipids and amino acids in membrane-traversing domains of ion channel proteins 37 , and hERG channel kinetics are sensitive to the cholesterol content of the plasma membrane 36 . Disruption of membrane cholesterol suppresses human and rat uterine contractions 38 .…”

Section: Discussionmentioning

confidence: 99%

Diminished hERG K+ channel activity facilitates strong human labour contractions but is dysregulated in obese women

et al. 2014

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Human ether-a-go-go-related gene (hERG) potassium channels determine cardiac action potential and contraction duration. Human uterine contractions are underpinned by an action potential that also possesses an initial spike followed by prolonged depolarization. Here we show that hERG channel proteins (a-conducting and b-inhibitory subunits) and hERG currents exist in isolated patch-clamped human myometrial cells. We show that hERG channel activity suppresses contraction amplitude and duration before labour, thereby facilitating quiescence. During established labour, expression of b-inhibitory protein is markedly enhanced, resulting in reduced hERG activity that is associated with an increased duration of uterine action potentials and contractions. Thus, changes in hERG channel activity contribute to electrophysiological mechanisms that produce contractions during labour. We also demonstrate that this system fails in women with elevated BMI, who have enhanced hERG activity as a result of low b-inhibitory protein expression, which likely contributes to the weak contractions and poor labour outcomes observed in many obese women necessitating caesarean delivery.

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“…12,14,[71][72][73][74] In adult canine ventricular tissue, KCNE2 and cERG are colocalized in cholesterol and sphingolipid-enriched membrane fractions. 75 hERG (and ERG from other mammals) is unusual in that it is part of the S4 superfamily of voltage-gated ion www.landesbioscience.com Channelschannels that includes the Kv a subunits, but it exhibits inward rectification similar to the Kir subunits. However, the mechanism in the two channel types is distinct: in hERG, activation is followed by extremely rapid inactivation that reduces peak current at depolarized potentials, 76 whereas in the Kir channels inward rectification occurs because of block by intracellular moieties at depolarized membrane potentials.…”

Section: Kcne2 In Cardiac Myocytes: Ventricular Repolarizationmentioning

confidence: 99%

KCNE2 and the K⁺channel

Abbott

2012

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Keywords: cardiac arrhythmia, choroid plexus, gastric acid, hypothyroidism, KCNQ1, MiRP1, thyroid KCNE2, originally designated MinK-related peptide 1 (MiRP1), belongs to a five-strong family of potassium channel ancillary (b) subunits that, despite the diminutive size of the family and its members, has loomed large in the field of ion channel physiology. KCNE2 dictates K + channel gating, conductance, a subunit composition, trafficking and pharmacology, and also modifies functional properties of monovalent cationnonselective HCN channels. The Kcne2 2/2 mouse exhibits cardiac arrhythmia and hypertrophy, achlorhydria, gastric neoplasia, hypothyroidism, alopecia, stunted growth and choroid plexus epithelial dysfunction, illustrating the breadth and depth of the influence of KCNE2, mutations which are also associated with human cardiac arrhythmias. Here, the modus operandi and physiological roles of this potent regulator of membrane excitability and ion secretion are reviewed with particular emphasis on the ability of KCNE2 to shape the electrophysiological landscape of both excitable and nonexcitable cells.

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Kv11.1 (ERG1) K⁺Channels Localize in Cholesterol and Sphingolipid Enriched Membranes and Are Modulated by Membrane Cholesterol

Cited by 55 publications

References 57 publications

Properties of WT and mutant hERG K⁺ channels expressed in neonatal mouse cardiomyocytes

Properties of WT and mutant hERG K⁺ channels expressed in neonatal mouse cardiomyocytes

Diminished hERG K+ channel activity facilitates strong human labour contractions but is dysregulated in obese women

KCNE2 and the K⁺channel

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Kv11.1 (ERG1) K+Channels Localize in Cholesterol and Sphingolipid Enriched Membranes and Are Modulated by Membrane Cholesterol

Cited by 55 publications

References 57 publications

Properties of WT and mutant hERG K+ channels expressed in neonatal mouse cardiomyocytes

Properties of WT and mutant hERG K+ channels expressed in neonatal mouse cardiomyocytes

Diminished hERG K+ channel activity facilitates strong human labour contractions but is dysregulated in obese women

KCNE2 and the K+channel

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Kv11.1 (ERG1) K⁺Channels Localize in Cholesterol and Sphingolipid Enriched Membranes and Are Modulated by Membrane Cholesterol

Properties of WT and mutant hERG K⁺ channels expressed in neonatal mouse cardiomyocytes

Properties of WT and mutant hERG K⁺ channels expressed in neonatal mouse cardiomyocytes

KCNE2 and the K⁺channel