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Voltage-gated K+ Channel (voltage-gated + k+_channel)

Distribution by Scientific Domains

Medical Sciences	50%

Selected Abstracts

Loss of the Potassium Channel ,-Subunit Gene, KCNAB2, Is Associated with Epilepsy in Patients with 1p36 Deletion Syndrome

EPILEPSIA, Issue 9 2001
Heidi A. Heilstedt
Summary: ,Purpose: Clinical features associated with chromosome 1p36 deletion include characteristic craniofacial abnormalities, mental retardation, and epilepsy. The presence and severity of specific phenotypic features are likely to be correlated with loss of a distinct complement of genes in each patient. We hypothesize that hemizygous deletion of one, or a few, critical gene(s) controlling neuronal excitability is associated with the epilepsy phenotype. Because ion channels are important determinants of seizure susceptibility and the voltage-gated K+ channel ,-subunit gene, KCNAB2, has been localized to 1p36, we propose that deletion of this gene may be associated with the epilepsy phenotype. Methods: Twenty-four patients were evaluated by fluorescence in situ hybridization with a probe containing KCNAB2. Clinical details were obtained by neurologic examination and EEG. Results: Nine patients are deleted for the KCNAB2 locus, and eight (89%) of these have epilepsy or epileptiform activity on EEG. The majority of patients have a severe seizure phenotype, including infantile spasms. In contrast, of those not deleted for KCNAB2, only 27% have chronic seizures, and none had infantile spasms. Conclusions: Lack of the , subunit would be predicted to reduce K+ channel,mediated membrane repolarization and increase neuronal excitability, suggesting a possible relation between loss of this gene and the development of seizures. Because some patients with seizures were not deleted for KCNAB2, there may be additional genes within 1p36 that contribute to epilepsy in this syndrome. Hemizygosity of this gene in a majority of monosomy 1p36 syndrome patients with epilepsy suggests that haploinsufficiency for KCNAB2 is a significant risk factor for epilepsy. [source]

AtKC1, a conditionally targeted Shaker-type subunit, regulates the activity of plant K+ channels

THE PLANT JOURNAL, Issue 1 2008
Geoffrey Duby
Summary Amongst the nine voltage-gated K+ channel (Kv) subunits expressed in Arabidopsis, AtKC1 does not seem to form functional Kv channels on its own, and is therefore said to be silent. It has been proposed to be a regulatory subunit, and to significantly influence the functional properties of heteromeric channels in which it participates, along with other Kv channel subunits. The mechanisms underlying these properties of AtKC1 remain unknown. Here, the transient (co-)expression of AtKC1, AKT1 and/or KAT1 genes was obtained in tobacco mesophyll protoplasts, which lack endogenous inward Kv channel activity. Our experimental conditions allowed both localization of expressed polypeptides (GFP-tagging) and recording of heterologously expressed Kv channel activity (untagged polypeptides). It is shown that AtKC1 remains in the endoplasmic reticulum unless it is co-expressed with AKT1. In these conditions heteromeric AtKC1-AKT1 channels are obtained, and display functional properties different from those of homomeric AKT1 channels in the same context. In particular, the activation threshold voltage of the former channels is more negative than that of the latter ones. Also, it is proposed that AtKC1-AKT1 heterodimers are preferred to AKT1-AKT1 homodimers during the process of tetramer assembly. Similar results are obtained upon co-expression of AtKC1 with KAT1. The whole set of data provides evidence that AtKC1 is a conditionally-targeted Kv subunit, which probably downregulates the physiological activity of other Kv channel subunits in Arabidopsis. [source]

Effect of K+ and Rb+ on the action of verapamil on a voltage-gated K+ channel, hKv1.3: implications for a second open state?

BRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2009
Z Kuras
Background and purpose:, Verapamil blocks current through the voltage-gated K+ channel Kv1.3 in the open and inactivated state of the channel but not the closed state. The binding site for verapamil was proposed to be close to the selectivity filter and the occupancy of the selectivity filter might therefore influence verapamil affinity. Experimental approach:, We investigated the influence of intra- and extracellular K+ and Rb+ on the effect of verapamil by patch-clamp studies, in COS-7 cells transfected with hKv1.3 channels. Key results:, Verapamil affinity was highest in high intracellular K+ concentrations ([K+]i) and lowest in low [Rb+]i, indicating an influence of intracellular cations on verapamil affinity. Experiments with a mutant channel (H399T), exhibiting a strongly reduced C-type inactivated state, demonstrated that part of this changed verapamil affinity in wild-type channels could be caused by altered C-type inactivation. External K+ and Rb+ could influence verapamil affinity by a voltage-dependent entry into the channel thereby modifying the verapamil off-rate and in addition causing a voltage-dependent verapamil off-rate. Conclusions and implications:, Recovery from verapamil block was mainly due to the voltage-dependent closing of channels (state-dependent block), implying a second open state of the channel. This hypothesis was confirmed by the dependency of the tail current time course on duration of the prepulse. We conclude that the wild-type hKv1.3 channel undergoes at least two different conformational changes before finally closing with a low verapamil affinity in one open state and a high verapamil affinity in the other open state. [source]

Modeling hERG and its Interactions with Drugs: Recent Advances in Light of Current Potassium Channel Simulations

CHEMMEDCHEM, Issue 4 2008
Maurizio Recanatini Prof.
Abstract The hERG K+ channel is responsible for the rapid delayed rectifier current in cardiac myocytes, and a block of its functioning may be related with the (inherited or drug-induced) long QT syndrome. For this reason, in recent times, some interest has arisen around computational studies aimed at developing hERG/drug models for the prediction of drug binding (docking) modes, in view of the assessment of the hERG blocking potential. On the other hand, voltage-gated K+ channels have been the subject of molecular simulations for several years, and rigorous protocols for studying the main aspects of their functions (permeation, gating, voltage sensing) have been published. In this article, we briefly introduce these classical computational works on K+ channels, and then review in depth the reports on the latest advanced modeling studies on hERG. The aim is to put the hERG modeling work in the more general context of the ion channel simulations field, to show the peculiarity of hERG on the one side, and also to indicate some possible new avenues in the use of modeling techniques to increase our knowledge of this important channel. [source]