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Heart Rhythm May 2008
Review
Topics: Action Potentials; Animals; Atrial Fibrillation; Humans; Potassium Channel Blockers; Potassium Channels
PubMed: 18452882
DOI: 10.1016/j.hrthm.2007.11.008 -
Biochemical and Biophysical Research... Jul 2002Several cytostatic agents are known to induce apoptosis in T-leukemic cells. Although a variety of studies show the central role of apoptosis in cytostatic drug-induced...
Several cytostatic agents are known to induce apoptosis in T-leukemic cells. Although a variety of studies show the central role of apoptosis in cytostatic drug-induced cell death, many molecular details require definition. Here, we demonstrate that cells genetically deficient for the potassium channel Kv1.3 are resistant to apoptosis initiated by the cytostatic drug actinomycin D. Retransfection of Kv1.3 restores sensitivity of the cells to actinomycin D. Cells lacking Kv1.3 fail to respond to actinomycin D with DNA fragmentation, release of cytochrome c, and loss of mitochondrial membrane potential (Delta Psi(m)), while cells functionally expressing Kv1.3 rapidly undergo those changes indicative for apoptosis. The data indicate a central role of the ion channel Kv1.3 in actinomycin D-triggered apoptosis.
Topics: Apoptosis; Cell Line; Dactinomycin; Humans; Kv1.3 Potassium Channel; Potassium Channels; Potassium Channels, Voltage-Gated
PubMed: 12150982
DOI: 10.1016/s0006-291x(02)00695-2 -
Archives of Neurology Apr 2003Efforts in basic neuroscience and studies of rare hereditary neurological diseases are partly motivated by the hope that such work can lead to better understanding of... (Review)
Review
Efforts in basic neuroscience and studies of rare hereditary neurological diseases are partly motivated by the hope that such work can lead to better understanding of and treatments for the common neurological disorders. An example is the progress that has resulted from identification of the genes that cause benign familial neonatal convulsions (BFNCs). Benign familial neonatal convulsions is a rare idiopathic, generalized epilepsy syndrome. In 1998, geneticists discovered that BFNC is caused by mutations in a novel potassium channel subunit, KCNQ2. Further work quickly revealed the sequences of 3 related brain channel genes KCNQ3, KCNQ4, and KCNQ5. Mutations in 2 of these genes were shown to cause BFNC (KCNQ3) and hereditary deafness (KCNQ4). Physiologists soon discovered that the KCNQ genes encoded subunits of the M-channel, a widely expressed potassium channel that mediates effects of modulatory neurotransmitters and controls repetitive neuronal discharges. Finally, pharmacologists discovered that the biological activities of 3 classes of compounds in development as treatments for Alzheimer disease, epilepsy, and stroke were mediated in part by effects on brain KCNQ channels. Cloned human KCNQ channels can now be used for high-throughput screening of additional drug candidates. Ongoing studies in humans and animal models will refine our understanding of KCNQ channel function and may reveal additional targets for therapeutic manipulation.
Topics: Epilepsy, Benign Neonatal; Humans; Indoles; Infant, Newborn; KCNQ Potassium Channels; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Mutation; Neurotransmitter Agents; Potassium Channels; Potassium Channels, Voltage-Gated
PubMed: 12707061
DOI: 10.1001/archneur.60.4.496 -
Current Pharmaceutical Design 2006Regulation of potassium (K+) channels evokes hyperpolarization or repolarization of the cell membrane to prevent or reverse cell excitability and is fundamental in the... (Review)
Review
Regulation of potassium (K+) channels evokes hyperpolarization or repolarization of the cell membrane to prevent or reverse cell excitability and is fundamental in the control of cellular activity throughout the range of tissue types within the human body. Genome projects predict that in excess of 80 K+ channel-related genes exist, resulting in a high degree of K+ channel diversity. In addition, dysfunction of K+ channels, as a result of mutations of the genes for the channel proteins or alterations in channel regulation, has been associated with the pathophysiology of diseases. These observations support K+ channels as therapeutic targets to regulate cellular homeostasis in pathophysiological conditions. Molecular cloning and expression of K+ channels offer important information in the identification of selective compounds to provide unique tissue management. Specific modulators have been identified for a limited number of K+ channel subtypes. Unfortunately the conversion of data obtained in the laboratory to success in the clinical setting has been limited. Tissue delivery of genes, in combination with drugs, may be an avenue enabling specific modulation of ion channel function and improved drug selectivity. Using specific examples (HERG, IKs, KCNQs, KCa, Kv1.3), issues regarding distribution, function and diversity related to advances made in the identification of modulators having therapeutic potential are discussed. The scope of this field is just emerging and the number of likely therapeutic indications for K+ channel modulators will increase as insight into the dynamics of expression of these channels in various diseases grows and the issue of the required selectivity is resolved.
Topics: Animals; Humans; Models, Biological; Potassium Channel Blockers; Potassium Channels
PubMed: 16472139
DOI: 10.2174/138161206775474477 -
The Journal of General Physiology Sep 2005The crystal structure of an open potassium channel reveals a kink in the inner helix that lines the pore (Jiang, Y.X., A. Lee, J.Y. Chen, M. Cadene, B.T. Chait, and R....
The crystal structure of an open potassium channel reveals a kink in the inner helix that lines the pore (Jiang, Y.X., A. Lee, J.Y. Chen, M. Cadene, B.T. Chait, and R. MacKinnon. 2002. Nature 417:523-526). The putative hinge point is a highly conserved glycine residue. We examined the role of the homologous residue (Gly466) in the S6 transmembrane segment of Shaker potassium channels. The nonfunctional alanine mutant G466A will assemble, albeit poorly, with wild-type (WT) subunits, suppressing functional expression. To test if this glycine residue is critical for activation gating, we did a glycine scan along the S6 segment in the background of G466A. Although all of these double mutants lack the higher-level glycosylation that is characteristic of mature Shaker channels, one (G466A/V467G) is able to generate voltage-dependent potassium current. Surface biotinylation shows that functional and nonfunctional constructs containing G466A express at comparable levels in the plasma membrane. Compared with WT channels, the shifted-glycine mutant has impairments in voltage-dependent channel opening, including a right-shifted activation curve and a decreased rate of activation. The double mutant has relatively normal open-channel properties, except for a decreased affinity for intracellular blockers, a consequence of the loss of the side chain of Val467. Control experiments with the double mutants M440A/G466A and G466A/V467A suggest that the flexibility provided by Gly466 is more important for channel function than its small size. Our results support roles for Gly466 both in biogenesis of the channel and as a hinge in activation gating.
Topics: Animals; Binding Sites; Cell Line; Epitopes; Glycine; Glycosylation; Humans; Ion Channel Gating; Membrane Potentials; Mutation; Oligopeptides; Oocytes; Peptides; Point Mutation; Potassium; Potassium Channel Blockers; Potassium Channels; Protein Structure, Secondary; Quaternary Ammonium Compounds; Shaker Superfamily of Potassium Channels; Transfection; Xenopus laevis
PubMed: 16103276
DOI: 10.1085/jgp.200509287 -
Biochemical and Biophysical Research... Jun 2003Previous studies suggested a central role of sphingomyelin- and cholesterol-enriched membrane rafts in the initiation of signaling via many receptors. Here, we...
Previous studies suggested a central role of sphingomyelin- and cholesterol-enriched membrane rafts in the initiation of signaling via many receptors. Here, we investigated the role of membrane rafts for the function of the voltage-gated potassium channel Kv1.3. We demonstrate that Kv1.3 localizes in the cell membrane to pre-existing small, sphingolipid- and cholesterol-enriched membrane rafts. Transformation of these small rafts to large ceramide-enriched membrane platforms was achieved by stimulation of the endogenous acid sphingomyelinase, addition of exogenous sphingomyelinase or treatment of the cells with C(16)-ceramide and resulted in clustering of Kv1.3 within ceramide-enriched membrane platforms and inhibition of the channel's activity. Likewise, disruption of pre-existing small rafts inhibited Kv1.3 activity. This indicates that intact small membrane rafts are required for Kv1.3 activity and an alteration of the lipid environment of rafts inhibits Kv1.3. These data, thus, may suggest a novel concept for the regulation of ion channels by the cell membrane composition.
Topics: Ceramides; Electric Conductivity; Humans; Jurkat Cells; Kv1.3 Potassium Channel; Lipids; Membrane Microdomains; Microscopy, Fluorescence; Patch-Clamp Techniques; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Sphingomyelin Phosphodiesterase; fas Receptor
PubMed: 12767914
DOI: 10.1016/s0006-291x(03)00763-0 -
The Journal of Urology Apr 2002We determined whether voltage gated K+ (KV) channels are expressed and functional in human detrusor smooth muscle
PURPOSE
We determined whether voltage gated K+ (KV) channels are expressed and functional in human detrusor smooth muscle
MATERIALS AND METHODS
Information on KV channels was obtained using electrophysiological patch clamp, immunofluorescence, Western blot and isometric tension recording techniques
RESULTS
Patch clamp recordings from detrusor cells revealed a Ca2+ independent K+ current that was activated by depolarization in a voltage range near the resting potential of detrusor smooth muscle. The current was inhibited by 3,4-diaminopyridine, a blocker of KV channels. Antibodies targeted to KValpha1 subunits revealed KV1.3 and KV1.6 expression in whole bladder tissue samples and specifically in detrusor smooth muscle cells. New specific blockers of KValpha1 channel currents (correolide and recombinant agitoxin-2) had a myogenic effect, characterized by increased amplitude of spontaneous contractions without an effect on the frequency of contractions or on resting baseline tension.
CONCLUSIONS
KValpha1 subunits are expressed and functionally important in human detrusor muscle.
Topics: Animals; Cells, Cultured; Humans; Kv1.1 Potassium Channel; Muscle, Smooth; Potassium Channels; Potassium Channels, Voltage-Gated; Rabbits; Urinary Bladder
PubMed: 11912453
DOI: No ID Found -
Bioorganic & Medicinal Chemistry Letters Aug 2003Traditional and hologram QSAR (HQSAR) models were developed for the prediction of hERG potassium channel affinities. The models were validated on three different test... (Comparative Study)
Comparative Study
Traditional and hologram QSAR (HQSAR) models were developed for the prediction of hERG potassium channel affinities. The models were validated on three different test sets including compounds with published patch-clamp IC(50) data and two subsets from the World Drug Index (compounds indicated to have ECG modifying adverse effect and drugs marked to be approved, respectively). Discriminant analysis performed on the full set of hERG data resulted in a traditional QSAR model that classified 83% of actives and 87% of inactives correctly. Analysis of our HQSAR model revealed it to be predictive in both IC(50) and discrimination studies.
Topics: Cation Transport Proteins; Databases, Factual; Discriminant Analysis; Ether-A-Go-Go Potassium Channels; Holography; Linear Models; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Quantitative Structure-Activity Relationship
PubMed: 12873512
DOI: 10.1016/s0960-894x(03)00492-x -
Cell May 1999
Review
Topics: Animals; Bacterial Proteins; Cell Membrane; Ion Channel Gating; Macromolecular Substances; Models, Molecular; Potassium Channels; Protein Structure, Secondary
PubMed: 10367883
DOI: 10.1016/s0092-8674(00)80765-5 -
Genomics Mar 1999
Topics: Animals; Blotting, Southern; Chromosome Mapping; DNA Primers; Haplotypes; Humans; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Mice; Polymorphism, Genetic; Potassium Channels; Potassium Channels, Voltage-Gated; Rats
PubMed: 10087209
DOI: 10.1006/geno.1998.5730