Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Potassium Channels”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 181 records · Page 10Linked to original sources
PubMed2006

Mitochondrial potassium channels: from pharmacology to function.

Mitochondrial potassium channels, such as ATP-regulated or large conductance Ca2+ -activated and voltage gated channels were implicated in cytoprotective phenomenon in different tissues. Basic effects of these channels activity include changes in mitochondrial matrix volume, mitochondrial respiration and membrane potential, and generation of reactive oxygen species. In this paper, we describe the pharmacological properties of mitochondrial potassium channels and their modulation by channel inhibitors and potassium channel openers. We also discuss potential side effects of these substances.

Adenosine Triphosphate↗
PubMed1992

Trypsin-sensitive, rapid inactivation of a calcium-activated potassium channel.

Most calcium-activated potassium channels couple changes in intracellular calcium to membrane excitability by conducting a current with a probability that depends directly on submembrane calcium concentration. In rat adrenal chromaffin cells, however, a large conductance, voltage- and calcium-activated potassium channel (BK) undergoes rapid inactivation, suggesting that this channel has a physiological role different than that of other BK channels. The inactivation of the BK channel, like that of the voltage-gated Shaker B potassium channel, is removed by trypsin digestion and channels are blocked by the Shaker B amino-terminal inactivating domain. Thus, this BK channel shares functional and possibly structural homologies with other inactivating voltage-gated potassium channels.

Adrenal Glands↗
PubMed2005

Direct binding of estradiol enhances Slack (sequence like a calcium-activated potassium channel) channels' activity.

17Beta-estradiol (E2) is a major neuroregulator, exerting both genomic and non-genomic actions. E2 regulation of Slack (sequence like a calcium-activated potassium channel) potassium channels has not been identified in the CNS. We demonstrate E2-induced activation of Slack channels, which display a unitary conductance of about 60 pS, are inhibited by intracellular calcium, and are abundantly expressed in the nervous system. In lipid bilayers derived from rat cortical neuronal membranes, E2 increases Slack open probability and appears to decrease channel inactivation. Additionally, E2 binds to the Slack channel and activates outward currents in human embryonic kidney-293 cells that express Slack channels but not classical estrogen receptors (i.e. ERalpha or ERbeta). Neither E2-induced activation nor the binding intensity of E2 to the Slack channel is blocked by tamoxifen, an ER antagonist/agonist. Thus, E2 activates a potassium channel, Slack, through a non-traditional membrane binding site, adding to known non-genomic mechanisms by which E2 exerts pharmacological and toxicological effects in the CNS.

Animals↗
PubMed1992

Alterations in macrophage free radical and tumor necrosis factor production by a potassium channel activator.

The potassium channel activator nicorandil, under evaluation for antianginal management, has been shown to decrease neutrophil respiratory burst. Since our laboratory has demonstrated that reactive oxygen species (ROS) increase tumor necrosis factor (TNF) production, we hypothesized that nicorandil might decrease TNF production from a lipopolysaccharide (LPS) challenge via reduction of respiratory burst. Macrophage viability and TNF production were determined after an 18-hr exposure to 5.0 micrograms/ml LPS and varying concentrations of nicorandil. Nicorandil was not toxic to macrophages below 12 mM (94 +/- 3% viability versus control) and decreased ROS and TNF production. Intracellular superoxide production decreased from 164 +/- 24 OD550 to 99 +/- 6 OD550 with 10 mM nicorandil and extracellular superoxide decreased from 3108 +/- 111 to 1760 +/- 210 nM. Hydrogen peroxide production was also decreased by 10 mM nicorandil. TNF production in response to 5 micrograms/ml LPS decreased from 6.8 +/- 0.6 to 2.7 +/- 0.4 ng/ml with 10 mM nicorandil. Northern and slot blot analyses demonstrate that nicorandil acts at a post-transcriptional site. These data imply that nicorandil decreases macrophage TNF production from an LPS challenge, possibly through a reduction in respiratory burst. Such compounds may prove useful in the treatment of conditions thought to be associated with free radical-lymphokine interactions such as ischemia-reperfusion injury, oxygen toxicity, adult respiratory distress syndrome, and septic shock.

Animals↗
PubMed2002

Interactions of phospholipids with the potassium channel KcsA.

The potassium channel KcsA from Streptomyces lividans has been reconstituted into bilayers of phosphatidylcholines and fluorescence spectroscopy has been used to characterize the response of KcsA to changes in bilayer thickness. The Trp residues in KcsA form two bands, one on each side of the membrane. Trp fluorescence emission spectra and the proportion of the Trp fluorescence intensity quenchable by I(-) hardly vary in the lipid chain length range C10 to C24, suggesting efficient hydrophobic matching between KcsA and the lipid bilayer over this range. Measurements of fluorescence quenching for KcsA reconstituted into mixtures of brominated and nonbrominated phospholipids have been analyzed to give binding constants of lipids for KcsA, relative to that for dioleoylphosphatidylcholine (di(C18:1)PC). Relative lipid binding constants increase by only a factor of three with increasing chain length from C10 to C22 with a decrease from C22 to C24. Strongest binding to di(C22:1)PC corresponds to a state in which the side chains of the lipid-exposed Trp residues are likely to be located within the hydrocarbon core of the lipid bilayer. It is suggested that matching of KcsA to thinner bilayers than di(C24:1)PC is achieved by tilting of the transmembrane alpha-helices in KcsA. Measurements of fluorescence quenching of KcsA in bilayers of brominated phospholipids as a function of phospholipid chain length suggest that in the chain length range C14 to C18 the Trp residues move further away from the center of the lipid bilayer with increasing chain length, which can be partly explained by a decrease in helix tilt angle with increasing bilayer thickness. In the chain length range C18 to C24 it is suggested that the Trp residues become more buried within the hydrocarbon core of the bilayer.

Bacterial Proteins↗
PubMed2000

Ion-Ion interactions at the selectivity filter. Evidence from K(+)-dependent modulation of tetraethylammonium efficacy in Kv2.1 potassium channels.

In the Kv2.1 potassium channel, binding of K(+) to a high-affinity site associated with the selectivity filter modulates channel sensitivity to external TEA. In channels carrying Na(+) current, K(+) interacts with the TEA modulation site at concentrations </=30 microM. In this paper, we further characterized the TEA modulation site and examined how varying K(+) occupancy of the pore influenced the interaction of K(+) with this site. In the presence of high internal and external [K(+)], TEA blocked 100% of current with an IC(50) of 1.9 +/- 0.2 mM. In the absence of a substitute permeating ion, such as Na(+), reducing access of K(+) to the pore resulted in a reduction of TEA efficacy, but produced little or no change in TEA potency (under conditions in which maximal block by TEA was just 32%, the IC(50) for block was 2.0 +/- 0.6 mM). The all-or-none nature of TEA block (channels were either completely sensitive or completely insensitive), indicated that one selectivity filter binding site must be occupied for TEA sensitivity, and that one selectivity filter binding site is not involved in modulating TEA sensitivity. At three different levels of K(+) occupancy, achieved by manipulating access of internal K(+) to the pore, elevation of external [K(+)] shifted channels from a TEA-insensitive to -sensitive state with an EC(50) of approximately 10 mM. Combined with previous results, these data demonstrate that the TEA modulation site has a high affinity for K(+) when only one K(+) is in the pore and a low affinity for K(+) when the pore is already occupied by K(+). These results indicate that ion-ion interactions occur at the selectivity filter. These results also suggest that the selectivity filter is the site of at least one low affinity modulatory effect of external K(+), and that the selectivity filter K(+) binding sites are not functionally interchangeable.

Amino Acid Substitution↗
PubMed1999

Protein kinase A phosphorylation alters Kvbeta1.3 subunit-mediated inactivation of the Kv1.5 potassium channel.

The human Kv1.5 potassium channel forms the IKur current in atrial myocytes and is functionally altered by coexpression with Kvbeta subunits. To explore the role of protein kinase A (PKA) phosphorylation in beta-subunit function, we examined the effect of PKA stimulation on Kv1.5 current following coexpression with either Kvbeta1.2 or Kvbeta1.3, both of which coassemble with Kv1.5 and induce fast inactivation. In Xenopus oocytes expressing Kv1.5 and Kvbeta1.3, activation of PKA reduced macroscopic inactivation with an increase in K+ current. Similar results were obtained using HEK 293 cells which lack endogenous K+ channel subunits. These effects did not occur when Kv1.5 was coexpressed with either Kvbeta1.2 or Kvbeta1.3 lacking the amino terminus, suggesting involvement of this region of Kvbeta1.3. Removal of a consensus PKA phosphorylation site on the Kvbeta1.3 NH2 terminus (serine 24), but not alternative sites in either Kvbeta1.3 or Kv1.5, resulted in loss of the functional effects of kinase activation. The effects of phosphorylation appeared to be electrostatic, as replacement of serine 24 with a negatively charged amino acid reduced beta-mediated inactivation, while substitution with a positively charged residue enhanced it. These results indicate that Kvbeta1.3-induced inactivation is reduced by PKA activation, and that phosphorylation of serine 24 in the subunit NH2 terminus is responsible.

Amino Acid Substitution↗
PubMed1993

Diuretic action of potassium channel blockers.

The availability of specific potassium channel blockers has made it possible to examine their effects along the nephron on fluid and electrolyte excretion. Recent experiments indicate that they modulate transepithelial sodium and potassium transport. In the thick ascending limb, potassium channel blockers, by interfering with potassium recycling across the apical cell membrane, reduce the activity of the sodium-2chloride-potassium cotransporter. In the initial and cortical collecting duct their inhibitory action on ATP-sensitive potassium channels reduces potassium secretion. Accordingly, tissue-specific potassium channel blockers are promising diuretic agents that may induce diuresis by inhibiting tubular sodium transport with only minimal loss of potassium.

Animals↗
PubMed1993

A peptide segment critical for sodium channel inactivation functions as an inactivation gate in a potassium channel.

The short cytoplasmic peptide segment connecting domains III and IV of voltage-gated sodium channels (III-IV linker) is essential for fast inactivation. To test the functional similarity between the III-IV linker and the potassium channel inactivation particle, we attached the III-IV linker to the amino terminus of a noninactivating potassium channel. This chimeric channel inactivated rapidly and displayed biophysical properties similar to Shaker A-type potassium channels. Recovery from inactivation in the chimeric channels was accelerated by high external potassium, consistent with the idea that potassium ions passing through the channel displaced the III-IV linker inactivation particle. A mutation that completely abolishes fast inactivation in rat brain sodium channels also completely abolished inactivation in the chimera. These results demonstrate that the sodium channel III-IV linker can function as a fast inactivation gate and suggest a functional relationship between the fast inactivation processes of sodium and potassium channels.

Amino Acid Sequence↗
PubMed2005

Biochemical characterization of the native Kv2.1 potassium channel.

Functional diversity of potassium channels in both prokaryotic and eukaryotic cells suggests multiple levels of regulation. Posttranslational regulation includes differential subunit assembly of homologous pore-forming subunits. In addition, a variety of modulatory subunits may interact with the pore complex either statically or dynamically. Kv2.1 is a delayed rectifier potassium channel isolated by expression cloning. The native polypeptide has not been purified, hence composition of the Kv2.1 channel complexes was not well understood. Here we report a biochemical characterization of Kv2.1 channel complexes from both recombinant cell lines and native rat brain. The channel complexes behave as large macromolecular complexes with an apparent oligomeric size of 650 kDa as judged by gel filtration chromatography. The molecular complexes have distinct biochemical populations detectable by a panel of antibodies. This is indicative of functional heterogeneity. Despite mRNA distribution in a variety of tissues, the native Kv2.1 polypeptides are more abundantly found in brain and have predominantly Kv2.1 subunits but not homologous Kv2.2 subunits. The proteins precipitated by anti-Kv2.1 and their physiological relevance are of interest for further investigation.

Amino Acid Sequence↗
PubMed2004

Molecular mechanism of voltage sensor movements in a potassium channel.

Voltage-gated potassium channels are six-transmembrane (S1-S6) proteins that form a central pore domain (4 x S5-S6) surrounded by four voltage sensor domains (S1-S4), which detect changes in membrane voltage and control pore opening. Upon depolarization, the S4 segments move outward carrying charged residues across the membrane field, thereby leading to the opening of the pore. The mechanism of S4 motion is controversial. We have investigated how S4 moves relative to the pore domain in the prototypical Shaker potassium channel. We introduced pairs of cysteines, one in S4 and the other in S5, and examined proximity changes between each pair of cysteines during activation, using Cd2+ and copper-phenanthroline, which crosslink the cysteines with metal and disulphide bridges, respectively. Modelling of the results suggests a novel mechanism: in the resting state, the top of the S3b-S4 voltage sensor paddle lies close to the top of S5 of the adjacent subunit, but moves towards the top of S5 of its own subunit during depolarization--this motion is accompanied by a reorientation of S4 charges to the extracellular phase.

Animals↗
PubMed1995

Silver as a probe of pore-forming residues in a potassium channel.

In voltage-dependent potassium channels, the molecular determinants of ion selectivity are found in the P (pore) region, a stretch of 21 contiguous residues. Cysteine was introduced at each P region position in a Shaker potassium channel. Residues projecting side chains into the pore were identified by means of channel inhibition by a sulfhydryl-reactive potassium ion analog, silver ion. The pattern of silver ion reactivity contradicts a beta barrel architecture of potassium channel pores.

Animals↗
PubMed1996

Modulation of muscle contractility during fatigue and recovery by ATP sensitive potassium channel.

The activity of ATP-sensitive potassium channels of skeletal muscle is controlled by changes in the bioenergetic state of the cell. These channels are inactive in unfatigued muscle and become activated during fatigue. It has been postulated that ATP-sensitive potassium channels shorten the action potential duration, increase the potassium efflux and contribute to the decrease in force during fatigue. Although blocking ATP-sensitive potassium channels during fatigue prolongs the action potential duration and decreases the potassium efflux as expected, it does not affect the rate of fatigue development as observed from the decrease in tetanic force. Even though such results are not consistent with the hypothesis that ATP-sensitive potassium channels contribute to the decrease in force during fatigue, a reduced capacity of skeletal muscles to recover their tetanic force following fatigue is also observed when ATP-sensitive potassium channels are blocked during fatigue, suggesting that these channels have a myoprotective effect. It is thus possible that removing this myoprotection during fatigue results in deleterious effects which counteract the expected slower decrease in force. However ATP-sensitive potassium channel openers also fall to affect the rate of fatigue development. Therefore, the results obtained so far do not support the hypothesis that ATP-sensitive potassium channels contribute to the decrease in force during fatigue.

Adenosine Triphosphate↗
PubMed2003

Identification of a heteromeric interaction that influences the rectification, gating, and pH sensitivity of Kir4.1/Kir5.1 potassium channels.

Heteromultimerization between different potassium channel subunits can generate channels with novel functional properties and thus contributes to the rich functional diversity of this gene family. The inwardly rectifying potassium channel subunit Kir5.1 exhibits highly selective heteromultimerization with Kir4.1 to generate heteromeric Kir4.1/Kir5.1 channels with unique rectification and kinetic properties. These novel channels are also inhibited by intracellular pH within the physiological range and are thought to play a key role in linking K+ and H+ homeostasis by the kidney. However, the mechanisms that control heteromeric K+ channel assembly and the structural elements that generate their unique functional properties are poorly understood. In this study we identify residues at an intersubunit interface between the cytoplasmic domains of Kir5.1 and Kir4.1 that influence the novel rectification and gating properties of heteromeric Kir4.1/Kir5.1 channels and that also contribute to their pH sensitivity. Furthermore, this interaction presents a structural mechanism for the functional coupling of these properties and explains how specific heteromeric interactions can contribute to the novel functional properties observed in heteromeric Kir channels. The highly conserved nature of this structural association between Kir subunits also has implications for understanding the general mechanisms of Kir channel gating and their regulation by intracellular pH.

Amino Acid Sequence↗
PubMed1996

[Regulation of muscarinic potassium channels].

Inwardly rectifying muscarinic potassium channels are directly activated by M2 muscarinic receptors in heart via a Pertussis toxin-sensitive G-protein. An intracellular second messenger is not involved in their activation. These channels undergo rapid (in about 30 seconds) and short-term desensitization. This desensitization is reversible in about 5 minutes. The molecular events underlying muscarinic potassium channels desensitization are still under study and apparently involve a phosphorylation/dephosphorylation process of one the proteins, i.e. the receptor, the G-protein or the channel itself.

Acetylcholine↗
PubMed2004

A thallium-sensitive, fluorescence-based assay for detecting and characterizing potassium channel modulators in mammalian cells.

Potassium channels have been identified as targets for a large number of therapeutic indications. The ability to use a high-throughput functional assay for the detection and characterization of small-molecule modulators of potassium channels is very desirable. However, present techniques capable of screening very large chemical libraries are limited in terms of data quality, temporal resolution, ease of use, and requirements for specialized instrumentation. To address these issues, the authors have developed a fluorescence-based thallium flux assay. This assay is capable of detecting modulators of both voltage and ligand-gated potassium channels expressed in mammalian cells. The thallium flux assay can use instruments standard to most high-throughput screening laboratories, and using such equipment has been successfully employed to screen large chemical libraries consisting of hundreds of thousands of compounds.

Biological Assay↗
PubMed2003

Identification of a COOH-terminal segment involved in maturation and stability of human ether-a-go-go-related gene potassium channels.

Mutations in the potassium channel encoded by the human ether-a-go-go-related gene (HERG) have been linked to the congenital long QT syndrome (LQTS), a cardiac disease associated with an increased preponderance of ventricular arrhythmias and sudden death. The COOH terminus of HERG harbors a large number of LQTS mutations and its removal prevents functional expression for reasons that remain unknown. In this study, we show that the COOH terminus of HERG is required for normal trafficking of the ion channel. We have identified a region critical for trafficking between residues 860 and 899 that includes a novel missense mutation at amino acid 861 (HERGN861I). Truncations or deletion of residues 860-899, characterized in six different expression systems including a cardiac cell line, resulted in decreased expression levels and an absence of the mature glycosylated form of the HERG protein. Deletion of this region did not interfere with the formation of tetramers but caused retention of the assembled ion channels within the endoplasmic reticulum. Consequently, removal of residues 860-899 resulted in the absence of the ion channels from the cell surface and a more rapid turnover rate than the wild type channels, which was evident very early in biogenesis. This study reveals a novel role of the COOH terminus in the normal biogenesis of HERG channels and suggests defective trafficking as a common mechanism for abnormal channel function resulting from mutations of critical COOH-terminal residues, including the LQTS mutant HERGN861I.

Animals↗
PubMed1995

Identification and molecular localization of a pH-sensing domain for the inward rectifier potassium channel HIR.

Inward rectifier potassium channels are found in the heart and CNS, where they are critical for the modulation and maintenance of cellular excitability. We present evidence that the inward rectifier potassium channel HIR is modulated by extracellular pH in the physiological range. We show that proton-induced changes in HIR single-channel conductance underlie the HIR pH sensitivity seen on the macroscopic level. We used chimeric and mutant channels to localize the molecular determinant of HIR pH sensitivity to a single residue, H117, in the M1-to-H5 linker region. This residue provides a molecular context that allows a titratable group to influence pore properties. We present evidence that this titratable group is one of two cysteines located in the M1-to-H5 and H5-to-M2 linkers.

Amino Acid Sequence↗