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PubMed2001

Vasopressin-induced protein kinase C-dependent superoxide generation contributes to atp-sensitive potassium channel but not calcium-sensitive potassium channel function impairment after brain injury.

BACKGROUND AND PURPOSE: Pial artery dilation in response to activators of the ATP-sensitive K(+) (K(ATP)) and calcium-sensitive K(+) (K(Ca)) channels is impaired after fluid percussion brain injury (FPI). Vasopressin, when coadministered with the K(ATP) and K(Ca) channel agonists cromakalim and NS1619 in a concentration approximating that observed in cerebrospinal fluid (CSF) after FPI, blunted K(ATP) and K(Ca) channel-mediated vasodilation. Vasopressin also contributes to impaired K(ATP) and K(Ca) channel vasodilation after FPI. In addition, protein kinase C (PKC) activation generates superoxide anion (O(2)(-)), which in turn contributes to K(ATP) channel impairment after FPI. We tested whether vasopressin generates O(2)(-) in a protein kinase C (PKC)-dependent manner, which could link vasopressin release to impaired K(ATP) and K(Ca) channel-induced pial artery dilation after FPI. METHODS: Injury of moderate severity (1.9 to 2.1 atm) was produced with the lateral FPI technique in anesthetized newborn pigs equipped with a closed cranial window. Superoxide dismutase-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O(2)(-) generation. RESULTS: Under sham injury conditions, topical vasopressin (40 pg/mL, the concentration present in CSF after FPI) increased superoxide dismutase-inhibitable NBT reduction from 1+/-1 to 23+/-4 pmol/mm(2). Chelerythrine (10(-7) mol/L, a PKC inhibitor) blunted such NBT reduction (1+/-1 to 9+/-2 pmol/mm(2)), whereas the vasopressin antagonist l-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid)2-(o-methyl)-Tyr-arginine vasopressin (MEAVP) blocked NBT reduction. Chelerythrine and MEAVP also blunted the NBT reduction observed after FPI (1+/-1 to 15+/-1, 1+/-1 to 4+/-1, and 1+/-1 to 5+/-1 pmol/mm(2) for sham-, chelerythrine-, and MEAVP-treated animals, respectively). Under sham injury conditions, vasopressin (40 pg/mL) coadministered with cromakalim or NS1619 blunted dilation in response to these K(+) channel agonists, whereas chelerythrine partially restored such impaired vasodilation for cromakalim but not NS1619. Cromakalim- and NS1619-induced pial artery dilation also was blunted after FPI. MEAVP partially protected dilation to both K(+) channel agonists after FPI, whereas chelerythrine did so for only cromakalim responses (for cromakalim at 10(-8) and 10(-6) mol/L, 13+/-1% and 23+/-1%, 2+/-1% and 5+/-1%, 9+/-1% and 15+/-2%, and 9+/-1% and 16+/-2% for sham-, FPI-, FPI-MEAVP-, and FPI-chelerythrine-pretreated animals, respectively). CONCLUSIONS: These data show that vasopressin, in concentrations present in CSF after FPI, increased O(2)(-) production in a PKC-dependent manner and contributes to such production after FPI. These data show that vasopressin contributes to K(ATP) but not K(Ca) channel function impairment in a PKC-dependent manner after FPI and suggest that vasopressin contributes to K(Ca) channel function impairment after FPI via a mechanism independent of PKC activation.

Adenosine Triphosphate↗
PubMed2001

Peripheral channelopathies as targets for potassium channel openers.

Potassium channel openers (KCOs) are important tools that are often used to gain a greater understanding of K(+) channels. Agents that can induce or maintain the opening of K(+) channels also offer a therapeutic approach to controlling of cell excitability and offer a means of producing stability in biological systems. The pathogenesis of a broad range of peripheral disorders (e.g., LQT syndrome, hypokalemic periodic paralysis, hyperinsulinism in infancy and erectile dysfunction) are associated with dysfunctional K(+) channels due to mutations in genes encoding channel proteins. The therapeutic potential of KCOs in peripheral K(+) channelopathies is discussed. The identification of K(+) channel subtype-specific openers offers discrete modulation of cellular systems creating a realistic therapeutic advance in the treatment of K(+) channelopathies.

Adenosine Triphosphatases↗
PubMedDate not supplied

The peptaibol antiamoebin as a model ion channel: similarities to bacterial potassium channels.

Antiamoebin (AAM) is a polypeptide antibiotic that is capable of forming ion channels in phospholipid membranes: planar bilayer studies have suggested the channels are octamers. The crystal structure of a monomeric form of AAM has provided the basis for molecular modelling of an octameric helical bundle channel. The channel model is funnel-shaped due to a substantial bend in the middle of the polypeptide chain caused by the presence of several imino acids. Inter-monomer hydrogen bonds orientate a ring of glutamine side chains to form a constriction in the pore lumen. The channel lumen is lined both by side chains of Gln11 and by polypeptide backbone carbonyl groups. Electrostatic calculations on the model are compatible with a channel that transports cations across membranes. The AAM channel model is compared with the crystal structures of two bacterial (KcsA andMthK) potassium channels. AAM and the potassium channels exhibit common functional features, such as cation-selectivity and similar single channel conductances. Common structural features include being multimers, each formed from a bundle of eight transmembrane helices, with lengths roughly comparable to the thickness of lipid bilayers. In addition, they all have aromatic amino acids that lie at the bilayer interfaces and which may aid in the stabilization of the transmembrane helices, as well as narrower constrictions that define the ion binding sites or selectivity filters in the pore lumen. The commonality of structural and functional features in these channels thus suggests that antiamoebin is a good, simple model for more complex bacterial and eukaryotic ion channels, capable of providing insight into details of the mechanisms of ion transport and multimeric channel stability.

Bacterial Proteins↗
PubMed1999

Overexpression of a Shaker-type potassium channel in mammalian central nervous system dysregulates native potassium channel gene expression.

The nervous system maintains a delicate balance between excitation and inhibition, partly through the complex interplay between voltage-gated sodium and potassium ion channels. Because K+ channel blockade or gene deletion causes hyperexcitability, it is generally assumed that increases in K+ channel gene expression should reduce neuronal network excitability. We have tested this hypothesis by creating a transgenic mouse that expresses a Shaker-type K+ channel gene. Paradoxically, we find that addition of the extra K+ channel gene results in a hyperexcitable rather than a hypoexcitable phenotype. The presence of the transgene leads to a complex deregulation of endogenous Shaker genes in the adult central nervous system as well as an increase in network excitability that includes spontaneous cortical spike and wave discharges and a lower threshold for epileptiform bursting in isolated hippocampal slices. These data suggest that an increase in K+ channel gene dosage leads to dysregulation of normal K+ channel gene expression, and it may underlie a mechanism contributing to the pathogenesis of human aneuploidies such as Down syndrome.

Animals↗
PubMed1997

Diversity of potassium channels contributing to differences in brain area-specific seizure susceptibility: sensitivity of different potassium channels to the epileptogenic agent pentylenetetrazol.

The effect of the epileptogenic agent pentylenetetrazol on eight cloned voltage-operated mammalian potassium channels (expressed in oocytes of Xenopus laevis) was investigated in order to contribute to an explanation for the brain area-specific differences in seizure susceptibility. Pentylenetetrazol increased the potassium currents at more negative and decreased them at more positive potentials for the channels of the Kv1 gene family, whereas for the other channels the currents were decreased over the whole potential range. The sensitivities of the different potassium channels to the epileptogenic agent were different. At a potential of 0 mV, for example, there were strong reductions for the Kv1.1, Kv1.4 and Kv2.1 currents, whereas the decrease was smaller for the Kv1.3 and Kv1.6 currents and was negligible for the Kv1.2, Kv1.5 and Kv3.4 currents. Correlating these data with the distribution patterns of the potassium channels in the hippocampus, the neocortex and the cerebellum (representing examples of brain areas of distinct seizure susceptibility) revealed that in brain areas with higher seizure susceptibility the overall sensitivity of the potassium channels to the epileptogenic agent is augmented. As a whole, the findings give the first evidence that the differences in distributions and properties of potassium channels contribute to differences in the seizure susceptibility of brain areas.

Animals↗
PubMed2000

An overview of the potassium channel family.

Potassium channels, tetrameric integral membrane proteins that form aqueous pores through which K+ can flow, are found in virtually all organisms; the genomes of humans, Drosophila, and Caenorhabditis elegans contain 30-100 K+ channel genes each. The structure of a bacterial K+ channel, sequence comparisons with other channels and electrophysiological measurements have enabled conclusions about the mechanism of gating and ion flow to be drawn for many other channels.

Animals↗
PubMed2001

Potassium channels as targets for ethanol: studies of G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) null mutant mice.

G-Protein-coupled inwardly rectifying potassium channels (GIRKs) regulate synaptic transmission and neuronal firing rates. Selective enhancement of GIRK2 function by intoxicating concentrations of ethanol was recently shown for recombinant homomeric and heteromeric channels. We proposed that specific behavioral actions of ethanol are due to activation of GIRK channels and that these behaviors would be reduced or eliminated in GIRK2 null mutant ("knockout") mice. Three behavioral effects of ethanol were absent in mutant mice as compared with wild-type littermates: stimulation of home cage (habituated) motor activity, anxiolytic action in elevated-plus maze test, and handling-induced convulsions (HIC) after an acute injection of ethanol. In contrast to these reductions of ethanol action, mutant mice displayed greater ethanol-stimulated activity in peripheral regions of an open field. There were no differences between mutant and wild-type mice for ethanol-induced sleep time, acute functional tolerance, or HIC following chronic matched consumption of a liquid diet. Ethanol preference and consumption were equal for wild-type and mutant mice using the standard two-bottle choice test with alternation of the bottles. However, this test was complicated by the strong side preference of the mice. When ethanol was presented constantly in their favored location, the consumption of ethanol was substantially higher for mutant than for wild-type mice. In the absence of ethanol, GIRK2 knockout mice showed more motor activity, less anxiety, and higher HIC. These results provide evidence that GIRK2 channels mediate specific behaviors, including anxiety and convulsions, and may influence effects of ethanol on these behaviors.

Alcohol Drinking↗
PubMed2005

The KCNQ5 potassium channel from mouse: a broadly expressed M-current like potassium channel modulated by zinc, pH, and volume changes.

The KCNQ proteins compose a sub-group of the voltage-activated potassium channel family. The family consists of five members (KCNQ1 to 5--also named Kv7.1 to Kv7.5) encoded by single genes, which all give rise to proteins forming slowly activating potassium-selective ion channels. The physiological importance of the KCNQ channel family is emphasized by the fact that mutations in four of the five genes have been linked to human pathologies (KCNQ1 to 4). Here, we present the cloning and characterization of a novel KCNQ5 ortholog from mouse isolated by homology cloning from total mouse brain RNA (GenBank accession number: AY679158). The predicted protein is 95% identical to human KCNQ5. Upon expression in Xenopus oocytes, these proteins form voltage-dependent slowly activating channels with half-maximal activation at -21 mV. Our functional characterization revealed three novel modes of modulation: pH-dependent potentiation by Zn2+ (EC50 = 21.8 microM at pH 7.4), inhibition by acidification (IC50 = 0.75 microM; pKa = 6.1), and regulation by small changes in cell volume. Furthermore, the channels are activated by the anti-convulsant drug retigabine (EC50 = 2.0 microM) and inhibited by the M-current blockers linopiridine and XE-991. Finally, real-time RT-PCR was used to quantify the expression profile in a wide range of mouse tissues. These experiments revealed a relatively broad expression pattern in the nervous system but also expression in other tissues. Highest overall expression levels were observed in cortex and hippocampus. This study shows that murine KCNQ5 channels, in addition to sharing biophysical and pharmacological characteristics with the human ortholog, are tightly regulated by physiological stimuli such as changes in extracellular Zn2+, pH, and tonicity, thus adding to the complex regulation of these channels.

Animals↗
PubMed1988

Evidence for two distinct potassium channels in avian granulosa cells.

Single-channel potassium currents were recorded in avian granulosa cells using the patch-clamp technique. Two types of channel were observed. The smaller of the two channels, gK1, had a conductance of 15 to 30 picosiemens (pS) and was voltage- and calcium-independent. Its null-current potential was -50 mV in the cell-attached recording mode. The other channel, gK2, was infrequently observed in the cell-attached configuration. Its conductance was between 160 and 195 pS. It could be activated by calcium on the cytoplasmic side of the membrane patch in the inside-out configuration. It was also voltage-dependent. These results suggest that fast transmembrane potassium movements may be involved in the membrane voltage regulation of granulosa cells, which in turn may play an important role in the modulation of steroidogenesis and other metabolic activities.

Animals↗
PubMed1990

Two different types of potassium channels in human skeletal muscle activated by potassium channel openers.

The inside-out patch clamp technique was used to record the effects of K+ channel openers (EMD 52692, RP 49356 and Cromakalim) on single channel currents in membrane blebs of human skeletal muscle. Two types of K+ channels were activated by these drugs: an ATP-sensitive K+ channel which was inhibited by 3 mM ATP and 5 microM Glibenclamide and an ATP insensitive K+ channel. The open probability of both types was strongly increased by K+ channel openers. Glibenclamide antagonized the action of the K+ channel openers.

Adenosine Triphosphate↗
PubMed1984

Single potassium channels with delayed rectifier behavior from lobster axon membranes.

Single-channel potassium currents from lobster axon membranes were studied in planar bilayers made from monolayers. Channel-opening events are grouped by time, forming bursts with an average duration of 4.5 ms. The mean open time at 0 mV is 1.8 ms. The frequency of bursts is voltage dependent, increasing e-fold per 12-16 mV. At sufficiently high positive voltages, channels inactivate. Measured from reversal potentials, channels discriminate against Na+ by a permeability ratio PNa/PK of 1:30. The channel is blocked by tetraethylammonium and nonyltrimethylammonium in a voltage-dependent manner and at concentrations similar to those used in whole-axon experiments. Voltage-dependent block by Cs+ suggests that more than one ion may occupy the channel simultaneously. The kinetics and selectivity of this channel suggest that purified axolemma contains active K+ channels that are likely to participate in delayed rectification in the lobster axon membrane.

Animals↗
PubMed1988

Gating kinetics of ATP-sensitive single potassium channels in myocardial cells depends on electromotive force.

ATP-sensitive single-channel potassium currents were studied in the membrane of rat ventricular myocytes. With an internal K+ concentration of [K+]i = 140 mM, the outwardly directed currents saturated at approximately 1.8 pA in the region of positive potentials independently of the external K+ concentration [K+]o, whereas an increase in [K+]i of up to 300 mM caused a positive shift in the region of current saturation (from approximately +40 mV to approximately +100 mV) and an increase in the level of the saturation up to approximately 4 pA. The openings of the channels appeared in bursts. Gating kinetics within the bursts were investigated. It was shown that the channel mean open (tau o) and closed (tau c) times during a burst depended primarily on the electromotive force (V-Vk) for potassium ions. For different [K+]o, tau o was maximal and tau c was minimal in the region of reversal potentials (Vrev); tau o decreased and tau c increased gradually with deviation of V from Vrev. Therefore we conclude that the gating properties of the ATP-sensitive K channels depend on the ion flux parameters.

Adenosine Triphosphate↗
PubMed1997

Effects of aranidipine, a novel calcium channel blocker, on mechanical responses of the isolated rat portal vein: comparison with typical calcium channel blockers and potassium channel openers.

We investigated the effects of aranidipine, a dihydropyridine-type Ca2+ channel blocker, on contractile responses to KCl and spontaneous contractions in isolated rat portal veins in comparison with those of the Ca2+ channel blockers, nifedipine, nicardipine, nitrendipine, diltiazem, and verapamil, and of the K+ channel openers, cromakalim and nicorandil. All the Ca2+ channel blockers concentration-dependently inhibited contractions induced by KCl. Interestingly, aranidipine was more potent against the low K+ (20 mM)-induced contraction than the high K+ (80 mM)-induced contraction, whereas the other Ca2+ channel blockers were equally potent against contractions induced by either concentration of KCl. Cromakalim and nicorandil were effective only on the low K(+)-induced contraction. In addition, all the Ca2+ channel blockers and the K+ channel openers tested inhibited the amplitude of spontaneous contractions of isolated rat portal vein. Tetraethylammonium (TEA), a classic K+ channel blocker, significantly attenuated the effect of aranidipine but not of other Ca2+ channel blockers on the spontaneous contractions. The cromakalim-induced inhibition of spontaneous contractions was antagonized by TEA. Thus aranidipine was found to be different from the typical Ca2+ channel blockers and in part similar to the K+ channel openers in inhibiting mechanical responses of isolated rat portal vein, suggesting that activation of K+ channels may in part in part be involved in the aranidipine-induced vasodilation.

Animals↗
PubMed2004

4-Chloro-benzo[F]isoquinoline (CBIQ) activates CFTR chloride channels and KCNN4 potassium channels in Calu-3 human airway epithelial cells.

1 Calu-3 cells have been used to investigate the actions of 4-chloro-benzo[F]isoquinoline (CBIQ) on short-circuit current (SCC) in monolayers, whole-cell recording from single cells and by patch clamping. 2 CBIQ caused a sustained, reversible and repeatable increase in SCC in Calu-3 monolayers with an EC50 of 4.0 microm. Simultaneous measurements of SCC and isotopic fluxes of 36Cl- showed that CBIQ caused electrogenic chloride secretion. 3 Apical membrane permeabilisation to allow recording of basolateral membrane conductance in the presence of a K+ gradient suggested that CBIQ activated the intermediate-conductance calcium-sensitive K(+)-channel (KCNN4). Permeabilisation of the basolateral membranes of epithelial monolayers in the presence of a Cl- gradient suggested that CBIQ activated the Cl(-)-channel CFTR in the apical membrane. 4 Whole-cell recording in the absence of ATP/GTP of Calu-3 cells showed that CBIQ generated an inwardly rectifying current sensitive to clotrimazole. In the presence of the nucleotides, a more complex I/V relation was found that was partially sensitive to glibenclamide. The data are consistent with the presence of both KCNN4 and CFTR in Calu-3. 5 Isolated inside-out patches from Calu-3 cells revealed clotrimazole-sensitive channels with a conductance of 12 pS at positive potentials after activation with CBIQ and demonstrating inwardly rectifying properties, consistent with the known properties of KCNN4. Cell-attached patches showed single channel events with a conductance of 7 pS and a linear I/V relation that were further activated by CBIQ by an increase in open state probability, consistent with known properties of CFTR. It is concluded that CBIQ activates CFTR and KCNN4 ion channels in Calu-3 cells.

Cell Line↗
PubMed2006

Computational recognition of potassium channel sequences.

MOTIVATION: Potassium channels are mainly known for their role in regulating and maintaining the membrane potential. Since this is one of the key mechanisms of signal transduction, malfunction of these potassium channels leads to a wide variety of severe diseases. Thus potassium channels are priority targets of research for new drugs, despite the fact that this protein family is highly variable and closely related to other channels, which makes it very difficult to identify new types of potassium channel sequences. RESULTS: Here we present a new method for identifying potassium channel sequences (PSM, Property Signature Method), which-in contrast to the known methods for protein classification-is directly based on physicochemical properties of amino acids rather than on the amino acids themselves. A signature for the pore region including the selectivity filter has been created, representing the most common physicochemical properties of known potassium channels. This string enables genome-wide screening for sequences with similar features despite a very low degree of amino acid similarity within a protein family.

Algorithms↗
PubMed2002

Potassium channel ontogeny.

Potassium channels are multi-subunit complexes, often composed of several polytopic membrane proteins and cytosolic proteins. The formation of these oligomeric structures, including both biogenesis and trafficking, is the subject of this review. The emphasis is on events in the endoplasmic reticulum (ER), particularly on how, where, and when K(+) channel polypeptides translocate and integrate into the bilayer, oligomerize and fold to form pore-forming units, and associate with auxiliary subunits to create the mature channel complex. Questions are raised with respect to the sequence of these events, when biogenic decisions are made, models for integration of K(+) channel transmembrane segments, crosstalk between the cell surface and ER, and recognition of compatible partner subunits. Also considered are determinants of subunit composition and stoichiometry, their consequence for trafficking, mechanisms for ER retention and export, and sequence motifs that direct channels to the cell surface. It is these mechanistic issues that govern the differential distributions of K(+) conductances at the cell surface, and hence the electrical activity of cells and tissues underlying both the physiology and pathophysiology of an organism.

Animals↗
PubMed1994

Inhibitory properties of NIP-121, a potassium channel opener, on high potassium- and norepinephrine-induced contraction and calcium mobilization in rat aorta.

We examined the effects of NIP-121, a potassium channel opener, on KCl- and norepinephrine (NE)-induced contraction, the phasic-contraction under the Ca(2+)-free condition and cytosolic free-Ca2+ mobilization using isolated rat aorta. NIP-121 as well as cromakalim inhibited, in the KCl- and NE-contractions concentration dependently. Glibenclamide, an ATP-sensitive potassium channel blocker, competitively reversed their inhibition. On the other hand, they did not inhibit the phasic-contractions induced by NE in Ca(2+)-free medium. In Fura-2-loaded rat aorta, NIP-121 inhibited only the late phase of the NE-induced cytosolic Ca2+ level ([Ca2+]cyt) increases that were inhibited by nicardipine. However, it did not inhibit the first [Ca2+]cyt increase, which was completely abolished by repeated applications of NE in Ca(2+)-free medium. Neither did it inhibit phorbol ester-induced contraction. The vasorelaxant mechanism of NIP-121 is attributable to the decrease in Ca2+ influx passing through the membrane Ca2+ permeable systems. In addition, inhibition of Ca2+ release from sarcoplasmic reticulum (SR) and of protein kinase C (PKC) activation may not be involved in vasorelaxation induced by NIP-121.

Animals↗
PubMed1991

Inhibition of aldosterone production and angiotensin action by drugs affecting potassium channels.

We screened potassium channel agonists and antagonists in a search for pharmacologic probes of the channels that mediate potassium's effects on adrenal zona glomerulosa cells. Suspensions of bovine cells were tested, and aldosterone was measured by radioimmunoassay. The most potent inhibitors were pinacidil, capsaicin, glyburide, and quinine. These reagents were more potent against aldosterone production than against cortisol production. Aldosterone produced under basal conditions, as well as that stimulated by potassium, angiotensin II, or dibutyryl cyclic AMP, was antagonized. The vasodilatory and aldosterone-inhibiting potencies of potassium channel reagents were very different. Candidate antihypertensives with potassium channel activity should be tested for adrenal inhibition.

Adenosine Triphosphate↗