Voltage-Gated Potassium Channels: Regulation by Accessory Subunits

Li, Yan; Um, Sung Yon; McDonald, Thomas V.

doi:10.1177/1073858406287717

Cited by 76 publications

(76 citation statements)

References 126 publications

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“…Several accessory subunits coassemble with the α-subunits in order to regulate the function of the ion channels (Li et al, 2006). Four different Kvβ subunits have been identified so far (Kvβ1 to Kvβ4); in addition, several variants may exist, e.g.…”

Section: Ion Channel Structure and Functionmentioning

confidence: 99%

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

Persson

Andersson

Duker

et al. 2007

European Journal of Pharmacology

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Atrial fibrillation (AF) is the most common tachyarrhythmia in the adult population and is a major cause of morbidity and mortality. AF can be terminated and sinus rhythm restored by prolonging the action potential duration (APD) and the refractory period. Unfortunately, antiarrhythmic agents that prolong the APD and increase the refractory period via selective inhibition of the rapid delayed rectifier potassium current (IK r ), i.e. class III antiarrhythmic drugs, are associated with an increased risk of the ventricular tachycardia Torsades de Pointes. AZD7009 is an antiarrhythmic agent with predominant actions on atrial electrophysiology that shows high antiarrhythmic efficacy and low proarrhythmic potential in animals and man. The aim of the current studies was to characterize the effect of AZD7009 on cardiac ion currents and APD in order to provide a mechanistic explanation for its predominant atrial effects and low proarrhythmic potential.The human cardiac ion channels hERG (IK r ), Kv1.5 (IK ur ), Kv4.3/KChIP2.2 (I to ), KvLQT1/minK (IK s ), Kir3.1/Kir3.4 (IK ACh ) and Nav1.5 (INa) were expressed in mammalian cells. Whole-cell currents were inhibited by AZD7009 with the following IC 50 values: hERG 0.6 μM, Nav1.5 8 μM, Kv4.3/KChIP2.2 24 μM, Kv1.5 27 μM, Kir3.1/Kir3.4 166 μM and KvLQT1/minK 193 μM. Whole-cell sodium and calcium currents were recorded in isolated rabbit atrial and ventricular myocytes using amphotericin B perforated patch. The late sodium current in rabbit atrial and ventricular myocytes was inhibited by AZD7009 in a concentration dependent way, with approximately 50% inhibition at 10 μM AZD7009. The L-type Ca 2+ current (ICa L ) in rabbit ventricular myocytes was inhibited with an IC 50 of 90 μM. Transmembrane action potentials were recorded in tissue pieces from rabbit atrium, ventricle and Purkinje fibre in control, during exposure to the selective IK r blocker E-4031 and to E-4031 in combination with AZD7009. In Purkinje fibres, but not in ventricular tissue, AZD7009 attenuated the E-4031-induced APD prolongation. In contrast, in atrial cells, AZD7009 further prolonged the APD. In addition, AZD7009 was able to suppress early afterdepolarisations (EADs) induced by E-4031 in Purkinje fibre preparations.In conclusion, AZD7009 delays repolarisation and increases refractoriness in atrial tissue through synergistic inhibition of IK r , I to , IK ur and INa, a mixed ion channel blockade that may underlie its high antiarrhythmic efficacy. Inhibition of the late sodium current, counteracting excessive APD prolongation and EADs in susceptible cells (midmyocardial and Purkinje cells), may explain the low proarrhythmic potential of AZD7009.

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Section: Ion Channel Structure and Functionmentioning

confidence: 99%

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

Persson

Andersson

Duker

et al. 2007

European Journal of Pharmacology

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“…In addition, these subunits regulate the surface expression and voltage sensitivity of Kv1 channels (reviewed in Ref. 6; see below).…”

Section: Kv ␤-Subunits Modify the Biophysical Properties Of Kv Channelsmentioning

confidence: 99%

A Marriage of Convenience: β-Subunits and Voltage-dependent K+ Channels

Torres

Morera

Carvacho

et al. 2007

Journal of Biological Chemistry

107

103

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The movement of ions across cell membranes is essential for a wide variety of fundamental physiological processes, including secretion, muscle contraction, and neuronal excitation. This movement is possible because of the presence in the cell membrane of a class of integral membrane proteins dubbed ion channels. Ion channels, thanks to the presence of aqueous pores in their structure, catalyze the passage of ions across the otherwise ion-impermeable lipid bilayer. Ion conduction across ion channels is highly regulated, and in the case of voltage-dependent K

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“…Remarkably, neither of these physiologically essential phenotypes resembles that of the KCNQ1 channel expressed alone, which activates rapidly over a hyperpolarized range of voltages (4, 5). Still other KCNE proteins coassemble with KCNQ1 to form heteromeric channels with distinct biophysical characteristics (7,8). This diverse array of gating schema allows this protein to play unique important roles in a vast number of systems in the body, including the heart, brain, inner ear, kidney, lungs, and intestine (3,9,10).…”

mentioning

confidence: 99%

Allosteric gating mechanism underlies the flexible gating of KCNQ1 potassium channels

Osteen

Barro-Soria

Robey

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

100

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KCNQ1 (Kv7.1) is a unique member of the superfamily of voltagegated K + channels in that it displays a remarkable range of gating behaviors tuned by coassembly with different β subunits of the KCNE family of proteins. To better understand the basis for the biophysical diversity of KCNQ1 channels, we here investigate the basis of KCNQ1 gating in the absence of β subunits using voltage-clamp fluorometry (VCF). In our previous study, we found the kinetics and voltage dependence of voltage-sensor movements are very similar to those of the channel gate, as if multiple voltage-sensor movements are not required to precede gate opening. Here, we have tested two different hypotheses to explain KCNQ1 gating: (i) KCNQ1 voltage sensors undergo a single concerted movement that leads to channel opening, or (ii) individual voltage-sensor movements lead to channel opening before all voltage sensors have moved. Here, we find that KCNQ1 voltage sensors move relatively independently, but that the channel can conduct before all voltage sensors have activated. We explore a KCNQ1 point mutation that causes some channels to transition to the open state even in the absence of voltage-sensor movement. To interpret these results, we adopt an allosteric gating scheme wherein KCNQ1 is able to transition to the open state after zero to four voltage-sensor movements. This model allows for widely varying gating behavior, depending on the relative strength of the opening transition, and suggests how KCNQ1 could be controlled by coassembly with different KCNE family members.) is a member of the superfamily of voltagegated potassium channels (K V ), which contain six transmembrane helices and form functional tetramers with four peripheral voltage-sensing domains surrounding a single potassiumselective pore domain (1). Much study spanning recent decades has focused on the detailed gating mechanisms of these molecular machines, establishing general principles of K V channel gating, as well as unique structural and functional properties that underlie the diverse physiological functions of different family members (2). Within the K V family, KCNQ1 displays a unique flexibility in its gating properties, depending on the tissue where it is expressed and the corresponding β subunit with which it coassembles: in the intestine KCNQ1/KCNE3 channels display voltage-independent current that supports chloride secretion (3), whereas in the heart, KCNQ1/KCNE1 channels display slowly activating voltage-dependent current that is critical to cardiac action potential repolarization (4-6). Remarkably, neither of these physiologically essential phenotypes resembles that of the KCNQ1 channel expressed alone, which activates rapidly over a hyperpolarized range of voltages (4, 5). Still other KCNE proteins coassemble with KCNQ1 to form heteromeric channels with distinct biophysical characteristics (7,8). This diverse array of gating schema allows this protein to play unique important roles in a vast number of systems in the body, including the heart, brain, inner ear, ...

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Voltage-Gated Potassium Channels: Regulation by Accessory Subunits

Cited by 76 publications

References 126 publications

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

A Marriage of Convenience: β-Subunits and Voltage-dependent K+ Channels

Allosteric gating mechanism underlies the flexible gating of KCNQ1 potassium channels

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