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Potential Repolarization (potential + repolarization)

Distribution by Scientific Domains
Medical Sciences40%

Kinds of Potential Repolarization

  • action potential repolarization
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    Selected Abstracts

    Acidosis Impairs the Protective Role of hERG K+ Channels Against Premature Stimulation

    JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 10 2010
    B.Sc., CHUN YUN DU M.B.
    Acidosis and the hERG K+ Channel.,Introduction: Potassium channels encoded by human ether-à-go-go-related gene (hERG) underlie the cardiac rapid delayed rectifier K+ channel current (IKr). Acidosis occurs in a number of pathological situations and modulates a range of ionic currents including IKr. The aim of this study was to characterize effects of extracellular acidosis on hERG current (IhERG), with particular reference to quantifying effects on IhERG elicited by physiological waveforms and upon the protective role afforded by hERG against premature depolarizing stimuli. Methods and Results: IhERG recordings were made from hERG-expressing Chinese Hamster Ovary cells using whole-cell patch-clamp at 37°C. IhERG during action potential (AP) waveforms was rapidly suppressed by reducing external pH from 7.4 to 6.3. Peak repolarizing current and steady state IhERG activation were shifted by ,+6 mV; maximal IhERG conductance was reduced. The voltage-dependence of IhERG inactivation was little-altered. Fast and slow time-constants of IhERG deactivation were smaller across a range of voltages at pH 6.3 than at pH 7.4, and the contribution of fast deactivation increased. A modest acceleration of the time-course of recovery of IhERG from inactivation was observed, but time-course of activation was unaffected. The amplitude of outward IhERG transients elicited by premature stimuli following an AP command was significantly decreased at lower pH. Computer simulations showed that after AP repolarization a subthreshold stimulus at pH 7.4 could evoke an AP at pH 6.3. Conclusion: During acidosis the contribution of IhERG to action potential repolarization is reduced and hERG may be less effective in counteracting proarrhythmogenic depolarizing stimuli. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1160-1169) [source]

    Sizing up Ethanol-Induced Plasticity: The Role of Small and Large Conductance Calcium-Activated Potassium Channels

    ALCOHOLISM, Issue 7 2009
    Patrick J. Mulholland
    Small (SK) and large conductance (BK) Ca2+ -activated K+ channels contribute to action potential repolarization, shape dendritic Ca2+spikes and postsynaptic responses, modulate the release of hormones and neurotransmitters, and contribute to hippocampal-dependent synaptic plasticity. Over the last decade, SK and BK channels have emerged as important targets for the development of acute ethanol tolerance and for altering neuronal excitability following chronic ethanol consumption. In this mini-review, we discuss new evidence implicating SK and BK channels in ethanol tolerance and ethanol-associated homeostatic plasticity. Findings from recent reports demonstrate that chronic ethanol produces a reduction in the function of SK channels in VTA dopaminergic and CA1 pyramidal neurons. It is hypothesized that the reduction in SK channel function increases the propensity for burst firing in VTA neurons and increases the likelihood for aberrant hyperexcitability during ethanol withdrawal in hippocampus. There is also increasing evidence supporting the idea that ethanol sensitivity of native BK channel results from differences in BK subunit composition, the proteolipid microenvironment, and molecular determinants of the channel-forming subunit itself. Moreover, these molecular entities play a substantial role in controlling the temporal component of ethanol-associated neuroadaptations in BK channels. Taken together, these studies suggest that SK and BK channels contribute to ethanol tolerance and adaptive plasticity. [source]

    SYMPOSIUM REVIEW: Revealing the structural basis of action of hERG potassium channel activators and blockers

    THE JOURNAL OF PHYSIOLOGY, Issue 17 2010
    Matthew Perry
    Human ether-á-go-go related gene (hERG) potassium (K+) channels play a critical role in cardiac action potential repolarization. This is due, in large part, to the unique gating properties of these channels, which are characterized by relatively slow activation and an unusually fast and voltage-dependent inactivation. A large number of structurally diverse compounds bind to hERG and carry an unacceptably high risk of causing arrhythmias. On the other hand, drugs that increase hERG current may, at least in principle, prove useful for treatment of long QT syndrome. A few blockers have been shown to increase hERG current at potentials close to the threshold for channel activation , a process referred to as facilitation. More recently, a novel group of hERG channel activators have been identified that slow deactivation and/or attenuate inactivation. Structural determinants for the action of two different types of activators have been identified. These compounds bind at sites that are distinct from each other and also separate from the binding site of high affinity blockers. They reveal not only novel ways of chemically manipulating hERG channel function, but also interactions between structural domains that are critical to normal activation and inactivation gating. [source]

    Mechanisms by which atrial fibrillation-associated mutations in the S1 domain of KCNQ1 slow deactivation of IKs channels

    THE JOURNAL OF PHYSIOLOGY, Issue 17 2008
    Lioara Restier
    The slow delayed rectifier K+ current (IKs) is a major determinant of action potential repolarization in the heart. IKs channels are formed by coassembly of pore-forming KCNQ1 ,-subunits and ancillary KCNE1 ,-subunits. Two gain of function mutations in KCNQ1 subunits (S140G and V141M) have been associated with atrial fibrillation (AF). Previous heterologous expression studies found that both mutations caused IKs to be instantaneously activated, presumably by preventing channel closure. The purpose of this study was to refine our understanding of the channel gating defects caused by these two mutations located in the S1 domain of KCNQ1. Site-directed mutagenesis was used to replace S140 or V141 with several other natural amino acids. Wild-type and mutant channels were heterologously expressed in Xenopus oocytes and channel function was assessed with the two-microelectrode voltage clamp technique. Long intervals between voltage clamp pulses revealed that S140G and V141M KCNQ1-KCNE1 channels are not constitutively active as previously reported, but instead exhibit extremely slow deactivation. The slow component of IKs deactivation was decreased 62-fold by S140G and 140-fold by the V141M mutation. In addition, the half-point for activation of these mutant IKs channels was ,50 mV more negative than wild-type channels. Other substitutions of S140 or V141 in KCNQ1 caused variable shifts in the voltage dependence of activation, but slowed IKs deactivation to a much lesser extent than the AF-associated mutations. Based on a published structural model of KCNQ1, S140 and V141 are located near E160 in S2 and R237 in S4, two charged residues that could form a salt bridge when the channel is in the open state. In support of this model, mutational exchange of E160 and R237 residues produced a constitutively open channel. Together our findings suggest that altered charge-pair interactions within the voltage sensor module of KCNQ1 subunits may account for slowed IKs deactivation induced by S140 or V141. [source]

    Tyrosine kinase and phosphatase regulation of slow delayed-rectifier K+ current in guinea-pig ventricular myocytes

    THE JOURNAL OF PHYSIOLOGY, Issue 2 2006
    Sergey Missan
    The objective of this study was to investigate the involvement of tyrosine phosphorylation in the regulation of the cardiac slowly activating delayed-rectifier K+ current (IKs) that is important for action potential repolarization. Constitutive IKs recorded from guinea-pig ventricular myocytes was suppressed by broad-spectrum tyrosine kinase (TK) inhibitors tyrphostin A23 (IC50, 4.1 ± 0.6 ,m), tyrphostin A25 (IC50, 12.1 ± 2.1 ,m) and genistein (IC50, 64 ± 4 ,m), but was relatively insensitive to the inactive analogues tyrphostin A1, tyrphostin A63, daidzein and genistin. IKs was unaffected by AG1478 (10 ,m), an inhibitor of epidermal growth factor receptor TK, and was strongly suppressed by the Src TK inhibitor PP2 (10 ,m) but not by the inactive analogue PP3 (10 ,m). The results of experiments with forskolin, H89 and bisindolylmaleimide I indicate that the suppression of IKs by TK inhibitors was not mediated via inhibition of (IKs -stimulatory) protein kinases A and C. To evaluate whether the suppression was related to lowered tyrosine phosphorylation, myocytes were pretreated with TK inhibitors and then exposed to the phosphotyrosyl phosphatase inhibitor orthovanadate (1 mm). Orthovanadate almost completely reversed the suppression of IKs induced by broad-spectrum TK inhibitors at concentrations around their IC50 values. We conclude that basal IKs is strongly dependent on tyrosine phosphorylation of Ks channel (or channel-regulatory) protein. [source]