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 919 records · Page 51Linked to original sources

Developmental expression of a voltage-dependent potassium channel (Kv3.1) in auditory neurons without cochlear input.

Kv3.1, a voltage-dependent potassium channel, has two forms, -a and -b, which differ in expression during development and at the onset of function in the auditory system. To determine whether cochlear nerve input could affect the expression of these two forms, cultures of the developing cochlear nucleus were explanted in the absence of the cochlear nerve at the beginning of cell migration (Hamburger-Hamilton stage 28-30), while neuroblasts continued to migrate onto the culture substrate. After 8, 15, and 22 days in vitro (three survival groups), cultures were immunostained with antibodies recognizing either both forms of Kv3.1 or only the -b form. Only young and newly migrated nerve cells were sampled. In the three survival groups, all nerve cells expressed Kv3.1, among which only 50% or less expressed the -b form. Some of the more differentiated multipolar cells expressed the -b form, but most were labeled with the antibody that recognizes both forms. Thus, in the absence of peripheral input, both forms of Kv3.1 appear at stages very early in development, although not all cells necessarily coexpress both forms. These results agree with other observations in the chick embryo in situ. They are consistent with previous work implicating Kv3.1 in cell migration during early development.

Age Factors↗

High-conductance potassium channels of the SLO family.

High-conductance, 'big' potassium (BK) channels encoded by the Slo gene family are among the largest and most complex of the extended family of potassium channels. The family of SLO channels apparently evolved from voltage-dependent potassium channels, but acquired a large conserved carboxyl extension, which allows channel gating to be altered in response to the direct sensing of several different intracellular ions, and by other second-messenger systems, such as those activated following neurotransmitter binding to G-protein-coupled receptors (GPCRs). This versatility has been exploited to serve many cellular roles, both within and outside the nervous system.

Animals↗

The interference of truncated with normal potassium channel subunits leads to abnormal behaviour in transgenic Drosophila melanogaster.

The Shaker locus of Drosophila melanogaster encodes a family of A-type potassium channel subunits. Shaker mutants behave as antimorphs in gene dosage tests. This behaviour is due to the production of truncated A-channel subunits. We propose that they interfere with the function of their normal counterpart by forming multimeric A-channel structures. This hypothesis was tested by constructing transgenic flies carrying a heat-inducible gene encoding a truncated A-type potassium channel subunit together with a normal wild type doses of A-type potassium channel subunits. The altered subunit leads at larval, pupal or adult stages to the transformation of wild type into Shaker flies. The transformed flies exhibited a heat-inducible abnormal leg shaking behaviour and a heat-inducible facilitated neurotransmitter release at larval neuromuscular junctions. By the overexpression of an aberrant A-channel subunit the normal behaviour of transgenic D. melanogaster can be altered in a predictable way.

Amino Acid Sequence↗

Kv1.3 potassium channels are localized in the immunological synapse formed between cytotoxic and target cells.

Membrane proteins of cytotoxic T cells specifically reorganize to form an immunological synapse (IS) on interaction with their specific target. In this paper, we investigated the redistribution of Kv1.3 channels, which are the dominant voltage-gated potassium channels, in the plasma membrane of allogen-activated human cytotoxic T lymphocytes (CTLs) on interacting with their specific target cells. Kv1.3 channels bearing a FLAG epitope were expressed in the CTLs and the cell-surface distribution of fluorescently labeled ion channels was determined from confocal laser-scanning microscopy images. FLAG epitope-tagged Kv1.3 channels showed a patchy distribution in CTLs not engaged with target cells, whereas the channels were accumulated in the IS formed between CTLs and specific target lymphocytes. Localization of Kv1.3 channels in the IS might open an unrevealed possibility in the regulation of ion channel activity by signaling molecules accumulated in the IS.

Cytotoxicity, Immunologic↗

Protection of rat pancreatic islets by potassium channel openers against alloxan, sodium nitroprusside and interleukin-1beta mediated suppression--possible involvement of the mitochondrial membrane potential.

AIMS/HYPOTHESIS: We aimed to study the effects of two K(ATP) channel openers (KCO), diazoxide and the more potent compound NNC 55-0118, on beta-cell suppression and/or toxicity induced by alloxan, sodium nitroprusside and IL-1beta. METHODS: Islets from rats were exposed to 0.3 mmol/l diazoxide or NNC 55-0118 for 30 min and either alloxan (0.5 mmol/l), sodium nitroprusside (0.5 mmol/l) or IL-1beta (12.5 or 25 U/ml) were added and the incubation continued for 30 min. Islets were then washed and incubated for 24 h before examination. RESULTS: After exposure to alloxan, islets showed reduced glucose oxidation rate and impaired glucose-stimulated insulin release. NNC 55-0118 counteracted the effects of alloxan, while diazoxide was less effective. After treatment with sodium nitroprusside, islet glucose oxidation rates were reduced and this was prevented by pretreatment with NNC 55-0118. In short-term experiments the potassium channel openers (KCOs) did not influence the IL-1beta effect on insulin secretion. However, long-term addition (24 h) of NNC 55-0118 counteracted IL-1beta induced inhibition of the glucose oxidation rate. It was shown, using the fluorescent probe JC-1, that the mitochondrial membrane potential was reduced by the potassium channel openers (KCOs), most strongly by NNC 55-0118. Nevertheless culture with KCOs for 72 h did not cause irreversible damage to the islets. CONCLUSION/INTERPRETATION: Potassium channel openers (KCOs), in particular NNC 55-0118, prevented the toxic effects of alloxan and sodium nitroprusside. IL-1beta mediated suppression was reduced by NNC 55-0118 provided the long-term addition of the potassium channel opener (KCO). The protective mechanism of potassium channel openers (KCOs) might involve a decrease of the mitochondrial membrane potential.

Alloxan↗

Hemodynamic profile of SKP-450, a new potassium-channel activator.

Hemodynamic profiles of SKP-450, a newly synthesized potassium-channel activator, were evaluated in conscious hypertensive rats of several types, and in anesthetized and conscious beagle dogs. In freely moving conscious rats, orally administered SKP-450 (0.03-0.3 mg/kg) dose-dependently decreased arterial pressure in spontaneously hypertensive rats (SHRs), renally hypertensive rats (RHRs), DOCA/salt-induced hypertensive rats (DHRs), and normotensive rats (NRs) with a greater potency than lemakalim except in DHRs (ED20 values: SKP-450, 0.021, 0.013, 0.024, and 0.034 mg/kg; lemakalim, 0.107, 0.018, 0.016, and 0.063 mg/kg, respectively). The blood pressure-reducing effects of SKP-450 reached their maximum within 30 min and lasted for approximately 4 h in all rats, and >6 h, particularly, in SHRs. In NRs, pretreatment with glibenclamide (20 mg/kg, i.v.) antagonized the hypotensive effect of SKP-450, whereas propranolol (2 mg/kg, i.v.) antagonized the tachycardiac response of SKP-450 (0.03 mg/kg, i.v.) without affecting its hypotensive response in NRs. In anesthetized beagle dogs, intraduodenally administered SKP-450 (0.003-0.03 mg/kg) dose-relatedly decreased arterial pressure (ED20 value, 0.007 mg/kg) for > or =3 h with its peak effects reached within 15 min and without significant changes in heart rate (HR). Antihypertensive effects of SKP-450 were accompanied by concurrent reduction in total peripheral resistance and dose-dependent increase in cardiac output. Indirect measures of myocardial oxygen demand such as rate-pressure product, tension-time index, and systolic time interval were dose-dependently decreased by SKP-450 without significant change in left ventricular dP/dt(max). SKP-450 significantly increased coronary blood flow and decreased coronary vascular resistance dose-dependently with a rapid onset of action and long duration of >4 h (maximal changes, 276 and 83.7% at 0.03 mg/kg, respectively). In conscious dogs, orally administered SKP-450 (0.03-0.3 mg/kg) produced a dose-related decrease in arterial pressure for > or =3 h, with its peak effects reached within 20 min (ED20 value, 0.030 mg/kg) accompanied by tachycardia. These results suggest that SKP-450 is a potent, orally active peripheral vasodilator activating ATP-sensitive potassium channels.

Anesthesia↗

Regulation of KChIP2 potassium channel beta subunit gene expression underlies the gradient of transient outward current in canine and human ventricle.

Expression of four members of the KChIP family of potassium channel beta subunits was examined in canine heart. Only one member of the gene family, KChIP2, was expressed in heart. There was a steep gradient of KChIP2 mRNA expression across the canine ventricular free wall. KChIP2 mRNA was 25-fold more abundant in the epicardium than in the endocardium, and this gradient paralleled the gradient in transient outward current (Ito) expression. In contrast, Kv4.3 potassium channel alpha subunit mRNA was expressed at equal levels across the ventricular wall. There was no difference in the pharmacological sensitivity of epicardial and endocardial Ito channels to flecainide, suggesting that the current is produced by the same channel in the two tissues. A similar gradient of KChIP2 expression was found across the ventricular wall of human heart, but not rat heart. It is concluded that transcriptional regulation of the KChIP2 beta subunit gene, rather than the Kv4.3 [alpha] subunit gene, is the primary determinant regulating the transmural gradient of Ito expression in the ventricular free wall of canine and human heart.

Animals↗

Downregulated REST transcription factor is a switch enabling critical potassium channel expression and cell proliferation.

Induction of K(Ca)3.1 (IKCa) potassium channel plays an important role in vascular smooth muscle cell proliferation. Here, we report that the gene encoding K(Ca)3.1 (KCNN4) contains a functional repressor element 1-silencing transcription factor (REST or NRSF) binding site and is repressed by REST. Although not previously associated with vascular smooth muscle cells, REST is present and recruited to the KCNN4 gene in situ. Significantly, expression of REST declines when there is cellular proliferation, showing an inverse relationship with functional K(Ca)3.1. Downregulated REST and upregulated K(Ca)3.1 are also evident in smooth muscle cells of human neointimal hyperplasia grown in organ culture. Furthermore, inhibition of K(Ca)3.1 suppresses neointimal formation, and exogenous REST reduces the functional impact of K(Ca)3.1. Here, we show REST plays a previously unrecognized role as a switch regulating potassium channel expression and consequently the phenotype of vascular smooth muscle cells and human vascular disease.

Animals↗

Molecular dynamics simulations of isolated transmembrane helices of potassium channels.

In the middle of the S6 helix in voltage-gated potassium channels there is a highly conserved Pro-Val-Pro motif, while the equivalent M2 helix of inward rectifier potassium channels contains a conserved glycine residue in a comparable position. The structural implications of these conserved motifs are of interest given the evidence that S6 and M2 are components of the lining of their respective pores. Multiple sequence alignment and TM helix prediction methods were used to define consensus regions for S6 and M2. Ensembles of 50 structures for each helix were generated by simulated annealing and restrained molecular dynamics. Time-dependent fluctuations of S6 and M2 were investigated by long time scale molecular dynamics simulations on representative members of each ensemble carried out in vacuo in the presence and absence of a hydrophobic potential that mimics a lipid bilayer. The results are discussed in terms of the structural basis of the kink in S6 and M2 and of a putative functional role for flexible helices as "molecular swivels."

Amino Acid Sequence↗

Potassium channel openers act through an activation of ATP-sensitive K+ channels in guinea-pig cardiac myocytes.

In a previous article (Escande et al. 1988a), we have shown that cromakalim (BRL 34915), a potassium channel opener (PCO), is a potent activator of ATP-sensitive K+ channels in cardiac cells. In the present article, the influence on K+ channels of two other potassium channel openers chemically unrelated to cromakalim, RP 49356 and pinacidil, has been investigated in patch-clamped isolated cardiac myocytes. In the whole-cell configuration, K+ currents were recorded in the presence of 50 microM TTX and 3 microM nitrendipine or 3 mM cobalt. Like cromakalim, RP 49356 or pinacidil activated a time-independent outward current at 33-35 degrees C but not at 19-21 degrees C, which showed little voltage-dependency in the potential range -60 to +60 mV. Its amplitude was a function of the agonist concentration, e.g. it was 2.1 +/- 0.4 nA at +60 mV with 30 microM RP 49356 and 4.3 +/- 0.8 nA with 300 microM. In control conditions, glibenclamide, a blocker of K+-ATP channels in pancreatic and heart cells, affected neither the inward rectifier, iK1, nor the delayed K+ current, iK. At 3 microM, glibenclamide fully prevented the effects of 300 microM RP 49356 or pinacidil. At lower concentrations, glibenclamide partially counteracted the activation by PCOs of a K+ current. In the cell-attached configuration, externally applied RP 49356 or pinacidil caused opening of large channels which reversed around O mV in a high K+ external medium. In inside-out patches, both RP 49356 or pinacidil activated K+-ATP channels by increasing the time period for which the channels remained in the open state. It is concluded that, like cromakalim, RP 49356 and pinacidil are potent activators of K+-ATP channels in cardiac myocytes.

Adenosine Triphosphate↗

Potassium channels in the vasodilating action of levosimendan on the human umbilical artery.

OBJECTIVE: Levosimendan is a calcium-sensitizing agent and inodilator working via potassium channels, which is under current investigation in the treatment of heart failure. We investigated the type of potassium channels that play a role on the dilatating effect of levosimendan on the contractile tones of the isolated human umbilical artery (HUA). METHODS: The response in the HUA was recorded isometrically by a force displacement transducer in isolated organ baths. Levosimendan was added to organ baths after precontraction with serotonin (5-HT, 1 microM). Levosimendan-induced relaxations were tested in the presence of the large conductance Ca2+-activated K+ channel inhibitor tetraethylammonium (TEA, 1 mM), the adenosine triphosphate (ATP)-sensitive K+ channel inhibitor glibenclamide (GLI, 10 microM), and the voltage-sensitive K+ channel inhibitor 4-aminopyridine (4-AP, 1 mM). All experiments were performed in solutions containing the cyclooxygenase inhibitor indomethacin (10 microM) and the nitric oxide synthase inhibitor L-NAME (100 microM). RESULTS: Levosimendan (10 nM to 3 microM) produced potent relaxation in the HUA. Vehicle had no significant relaxant effect. The relaxation to levosimendan was not affected by the K+ channel inhibitor, GLI. However, 4-AP (1 mM) and TEA (1 mM) inhibited levosimendan-induced relaxation significantly (P <.05). CONCLUSION: These results show that levosimendan effectively and directly decreases the tone of the HUA. The mechanism of this levosimendan-induced relaxation in the HUA appears in part to be due to voltage-gated and large conductance Ca2+-activated K+ channel opening action.

Cardiotonic Agents↗

Interaction with 14-3-3 proteins promotes functional expression of the potassium channels TASK-1 and TASK-3.

The two-pore-domain potassium channels TASK-1, TASK-3 and TASK-5 possess a conserved C-terminal motif of five amino acids. Truncation of the C-terminus of TASK-1 strongly reduced the currents measured after heterologous expression in Xenopus oocytes or HEK293 cells and decreased surface membrane expression of GFP-tagged channel proteins. Two-hybrid analysis showed that the C-terminal domain of TASK-1, TASK-3 and TASK-5, but not TASK-4, interacts with isoforms of the adapter protein 14-3-3. A pentapeptide motif at the extreme C-terminus of TASK-1, RRx(S/T)x, was found to be sufficient for weak but significant interaction with 14-3-3, whereas the last 40 amino acids of TASK-1 were required for strong binding. Deletion of a single amino acid at the C-terminal end of TASK-1 or TASK-3 abolished binding of 14-3-3 and strongly reduced the macroscopic currents observed in Xenopus oocytes. TASK-1 mutants that failed to interact with 14-3-3 isoforms (V411*, S410A, S410D) also produced only very weak macroscopic currents. In contrast, the mutant TASK-1 S409A, which interacts with 14-3-3-like wild-type channels, displayed normal macroscopic currents. Co-injection of 14-3-3zeta cRNA increased TASK-1 current in Xenopus oocytes by about 70 %. After co-transfection in HEK293 cells, TASK-1 and 14-3-3zeta (but not TASK-1DeltaC5 and 14-3-3zeta) could be co-immunoprecipitated. Furthermore, TASK-1 and 14-3-3 could be co-immunoprecipitated in synaptic membrane extracts and postsynaptic density membranes. Our findings suggest that interaction of 14-3-3 with TASK-1 or TASK-3 may promote the trafficking of the channels to the surface membrane.

14-3-3 Proteins↗

The structure of the potassium channel: molecular basis of K+ conduction and selectivity.

The potassium channel from Streptomyces lividans is an integral membrane protein with sequence similarity to all known K+ channels, particularly in the pore region. X-ray analysis with data to 3.2 angstroms reveals that four identical subunits create an inverted teepee, or cone, cradling the selectivity filter of the pore in its outer end. The narrow selectivity filter is only 12 angstroms long, whereas the remainder of the pore is wider and lined with hydrophobic amino acids. A large water-filled cavity and helix dipoles are positioned so as to overcome electrostatic destabilization of an ion in the pore at the center of the bilayer. Main chain carbonyl oxygen atoms from the K+ channel signature sequence line the selectivity filter, which is held open by structural constraints to coordinate K+ ions but not smaller Na+ ions. The selectivity filter contains two K+ ions about 7.5 angstroms apart. This configuration promotes ion conduction by exploiting electrostatic repulsive forces to overcome attractive forces between K+ ions and the selectivity filter. The architecture of the pore establishes the physical principles underlying selective K+ conduction.

Amino Acid Sequence↗

Mice disrupted for the KvLQT1 potassium channel regulator IsK gene accumulate mature T cells.

The IsK protein associates with KvLQT1 potassium channels to generate the slow component of the outward rectifying K(+) current involved in human cardiac repolarization. Mutations in either KCNE1 (encoding IsK) or KCNQ1 (encoding KvLQT1) genes have been associated with the long QT syndrome, a genetic disorder leading to prolonged cardiac repolarization and sudden death. We now report that the IsK protein is also involved in mature T cell homeostasis. In KCNE1 gene knockout mice, we observed a significant increase in the T cell compartment. Thymus and peripheral lymphoid organs of KCNE1-/- mice displayed a significant increase in mature T cells. The immunological phenotype of KCNE1-/- is age-dependent and only expressed in adult mice. Both IsK and KvLQT1 mRNA are expressed in murine thymus. Our data suggest that, in addition to its role in myocardial repolarization, the IsK-KvLQT1 tandem also plays a crucial role in T cell homeostasis.

Aging↗

Potassium channels Kv1.1, Kv1.2 and Kv1.6 influence excitability of rat visceral sensory neurons.

Voltage-gated potassium channels, Kv1.1, Kv1.2 and Kv1.6, were identified as PCR products from mRNA prepared from nodose ganglia. Immunocytochemical studies demonstrated expression of the proteins in all neurons from ganglia of neonatal animals (postnatal days 0-3) and in 85-90 % of the neurons from older animals (postnatal days 21-60). In voltage clamp studies, alpha-dendrotoxin (alpha-DTX), a toxin with high specificity for these members of the Kv1 family, was used to examine their contribution to K(+) currents of the sensory neurons. alpha-DTX blocked current in both A- and C-type neurons. The current had characteristics of a delayed rectifier with activation positive to -50 mV and little inactivation during 250 ms pulses. In current-clamp experiments alpha-DTX, used to eliminate the current, had no effect on resting membrane potential and only small effects on the amplitude and duration of the action potential of A- and C-type neurons. However, there were prominent effects on excitability. alpha-DTX lowered the threshold for initiation of discharge in response to depolarizing current steps, reduced spike after-hyperpolarization and increased the frequency/pattern of discharge of A- and C-type neurons at membrane potentials above threshold. Model simulations were consistent with these experimental results and demonstrated how the other major K(+) currents function in response to the loss of the alpha-DTX-sensitive current to effect these changes in action potential wave shape and discharge.

Algorithms↗

Molecular identification and characterisation of the human eag2 potassium channel.

We report the molecular cloning from foetal brain of the human potassium channel heag2. The cDNA encodes a protein of 988 amino acids, 73% identical to heag1. Heag2 is expressed in the brain, but is also found in a range of tissues including skeletal muscle. In oocytes, the channel is a non-inactivating outward rectifier, with dependence of activation rate on holding potential. Compared with heag1, the conductance-voltage curve for heag2 was shifted to the left, the voltage sensitivity was less, activation kinetics were different, and the sensitivity to terfenadine was lower. The heag2 channel may have important physiological roles.

Amino Acid Sequence↗

Inhibition of HERG potassium channel current by the class 1a antiarrhythmic agent disopyramide.

The Class 1a antiarrhythmic drug disopyramide (DISO) is associated with 'acquired' prolongation of the QT interval of the electrocardiogram (ECG). This potentially proarrhythmic effect is likely to reflect drug actions on ion channels involved in ventricular action potential repolarisation. In this study, we examined the effects of DISO on potassium channels encoded by HERG, as this K channel type has been implicated in both congenital and acquired long-QT syndromes (LQTS). Chinese hamster ovary cells were transiently transfected with HERG cDNA for subsequent whole cell patch clamp recording. HERG tail currents recorded at -40 mV following test pulses to +30 mV were inhibited in a dose-dependent fashion by DISO concentrations within the clinical range (IC50 = 7.23 +/- 0.72 microM; mean +/- SEM). Experiments with 10 microM DISO indicated that the degree of HERG blockade showed some voltage dependence. Further data obtained using an 'envelope of tails' protocol (pulse potential +40 mV) were consistent with a significant role for open-channel blockade at lower drug concentrations. At higher concentrations it is possible that blockade may have involved drug binding to both resting and open channels. Inhibition of the inactivation-deficient mutant HERG-S631A was comparable to that seen for wild-type HERG. Therefore, channel inactivation was not obligatory for DISO to exert its effect. Native delayed rectifier tail currents from rabbit isolated ventricular myocytes were also inhibited by DISO. We conclude (a) that DISO inhibits HERG encoded potassium channels at clinically relevant concentrations and (b) that this action may constitute the molecular basis for acquired LQTS associated with this drug.

Animals↗