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Results for “Delayed Rectifier Potassium Channels”

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PubMed2006

Modulation of the pancreatic islet beta-cell-delayed rectifier potassium channel Kv2.1 by the polyunsaturated fatty acid arachidonate.

Glucose stimulates both insulin secretion and hydrolysis of arachidonic acid (AA) esterified in membrane phospholipids of pancreatic islet beta-cells, and these processes are amplified by muscarinic agonists. Here we demonstrate that nonesterified AA regulates the biophysical activity of the pancreatic islet beta-cell-delayed rectifier channel, Kv2.1. Recordings of Kv2.1 currents from INS-1 insulinoma cells incubated with AA (5 mum) and subjected to graded degrees of depolarization exhibit a significantly shorter time-to-peak current interval than do control cells. AA causes a rapid decay and reduced peak conductance of delayed rectifier currents from INS-1 cells and from primary beta-cells isolated from mouse, rat, and human pancreatic islets. Stimulating mouse islets with AA results in a significant increase in the frequency of glucose-induced [Ca(2+)] oscillations, which is an expected effect of Kv2.1 channel blockade. Stimulation with concentrations of glucose and carbachol that accelerate hydrolysis of endogenous AA from islet phosphoplipids also results in accelerated Kv2.1 inactivation and a shorter time-to-peak current interval. Group VIA phospholipase A(2) (iPLA(2)beta) hydrolyzes beta-cell membrane phospholipids to release nonesterified fatty acids, including AA, and inhibiting iPLA(2)beta prevents the muscarinic agonist-induced accelerated Kv2.1 inactivation. Furthermore, glucose and carbachol do not significantly affect Kv2.1 inactivation in beta-cells from iPLA(2)beta(-/-) mice. Stably transfected INS-1 cells that overexpress iPLA(2)beta hydrolyze phospholipids more rapidly than control INS-1 cells and also exhibit an increase in the inactivation rate of the delayed rectifier currents. These results suggest that Kv2.1 currents could be dynamically modulated in the pancreatic islet beta-cell by phospholipase-catalyzed hydrolysis of membrane phospholipids to yield non-esterified fatty acids, such as AA, that facilitate Ca(2+) entry and insulin secretion.

Animals↗
PubMed1994

Characterization of the calcium-sensitive voltage-gated delayed rectifier potassium channel in isolated guinea pig hepatocytes.

The voltage-dependent K+ channel was examined in enzymatically isolated guinea pig hepatocytes using whole-cell, excised outside-out and inside-out configurations of the patch-clamp technique. The resting membrane potential in isolated hepatocytes was -25.3 +/- 4.9 mV (n = 40). Under the whole-cell voltage-clamp, the time-dependent delayed rectifier outward current was observed at membrane potentials positive to -20 mV at physiological temperature (37 degrees C). The reversal potential of the current, as determined from tail current measurements, shifted by approximately 57 mV per 10-fold change in the external K+ concentration. In addition, the current did not appear when K+ was replaced with Cs+ in the internal and external solutions, indicating that the current was carried by K+ ions. The envelope test of the tails demonstrated that the growth of the tail current followed that of the current activation. The ratio between the activated current and the tail amplitude was constant during the depolarizing step. The time course of growth and deactivation of the tail current were best described by a double exponential function. The current was suppressed in Ca(2+)-free, 5 mM EGTA internal or external solution (pCa > 9). The activation curve (P infinity curve) was not shifted by changing the internal Ca2+ concentration ([Ca2+]i). The current was inhibited by bath application of 4-aminopyridine or apamin. alpha 1-Adrenergic stimulation with noradrenaline enhanced the current but beta-adrenergic stimulation with isoproterenol had no effect on the current. In single-channel recordings from outside-out patches, unitary current activity was observed by depolarizing voltage-clamp steps whose slope conductance was 9.5 +/- 2.2 pS (n = 10). The open time distribution was best described by a single exponential function with the mean open lifetime of 18.5 +/- 2.6 ms (n = 14), while at least two exponentials were required to fit the closed time distributions with a time constant for the fast component of 2.0 +/- 0.3 ms (n = 14) and that for the slow component of 47.7 +/- 5.9 ms (n = 14). Ensemble averaged current exhibited delayed rectifier nature which was consistent with whole-cell measurements. In excised inside-out patch recordings, channel open probability was sensitive to [Ca2+]i. The concentration of Ca2+ at the half-maximal activation was 0.031 microM. These results suggest that guinea pig hepatocytes possess voltage-gated delayed rectifier K+ channels which are modified by intracellular Ca2+.

4-Aminopyridine↗
PubMed1998

Thiamine and its derivatives inhibit delayed rectifier potassium channels of rat cultured cortical neurons.

We examined the effects of thiamine and its derivatives on voltage-gated ion channels of neuronal cells isolated from fetal forebrain cortex and cultured for 6-14 days. Under the whole-cell voltage clamp, thiamine tetrahydrofurfuryl disulfide (TTFD), a membrane-permeable derivative of thiamine, inhibited the delayed rectifier K+ current (IK) in a concentration-dependent manner (10(-4)-10(-3) M). The IK-suppressing effect was also observed by internal perfusion with 1 mM thiamine, but not by the external application of thiamine, indicating the poor permeability of thiamine through the cell membrane. However, thiamine which was applied directly to the intracellular side of patch membranes in the inside-out configuration failed to decrease the open probability of the single IK channel. In contrast, thiamine diphosphate decreased both the open probability and the open-time of the channel without changing the single channel conductance. These results suggest that phosphorylated thiamine can function as an endogenous K+ channel blocker in neuronal cells. TTFD, when applied extracellularly at a concentration of 1 mM, prolonged the action potential (AP) duration of neurons (172.8 +/- 6.6%) without changing the resting membrane potential or AP amplitude, while the same concentration of thiamine did not influence any parameters of the AP, implying that TTFD may cause the potentiation of neuronal AP through the inhibition of IK.

Animals↗
PubMed1991

Delayed-rectifier potassium channel activity in isolated membrane patches of guinea pig ventricular myocytes.

When the patch-clamp technique was used, a slowly activating, time-dependent outward current was identified in both cell-attached and excised membrane patches obtained from guinea pig ventricular myocytes. This macroscopic patch current was present in approximately 50% of patches studied and could be observed both in the presence and absence of unitary single channel activity (i.e., ATP-sensitive K+ channels). The time course of activation of the patch current resembled that of the whole cell delayed-rectifier K+ current (IK) recorded under similar ionic conditions, and the patch current and IK were activated over a similar membrane potential range. The time-dependent patch current could be eliminated when the Nernst potential for K+ equaled that of the pulse voltage. The patch current was inhibited by external addition of the tertiary ammonium compound LY 97241 (50 microM) and was augmented after internal application of the catalytic subunit of adenosine 3',5'-cyclic monophosphate-dependent protein kinase (500 nM). Deactivating tail currents with kinetics similar to those of IK could be recorded to cell-attached and excised patches. Unitary single channel events underlying the time-dependent patch current could not be resolved despite various attempts to increase single channel conductance. Thus our results suggest that a major component of delayed rectification in guinea pig ventricular cells is due to the activity of a high-density, extremely low conductance K+ channel.

Adenosine Triphosphate↗
PubMed1990

Cloning and expression of cDNA and genomic clones encoding three delayed rectifier potassium channels in rat brain.

Rat brain cDNA and genomic clones encoding three K+ channels, Kv1, Kv2, and Kv3, have been isolated by screening with Shaker probes and encode proteins of 602, 530, and 525 amino acids. Each of the deduced protein sequences contains six hydrophobic domains (including an S4-type region characteristic of many voltage-gated channels) and are 68%-72% identical to each other overall. Transcripts of approximately 3.5, approximately 6.5, and approximately 9.5 kb encode Kv1, Kv2, and Kv3, respectively. The Kv2 mRNA is expressed only in brain, whereas the Kv1 and Kv3 transcripts are found in several other tissues as well. There is a marked increase in the amount of Kv1 mRNA in cardiac tissue during development and a similar, but less pronounced, increase of both this mRNA and the Kv2 transcript in brain. RNAs synthesized in vitro from the three clones induce voltage- and time-dependent, delayed rectifier-like K+ currents when injected into Xenopus oocytes, demonstrating that they encode functional K+ channels.

Amino Acid Sequence↗
PubMed1996

Activation of delayed rectifier potassium channels in canine proximal colon by vasoactive intestinal peptide.

1. Vasoactive intestinal peptide (VIP) inhibits phasic contractions and tone of gastrointestinal smooth muscles. This study examines electrical mechanisms that may mediate the inhibitory actions of VIP. 2. Electrical slow waves were recorded from canine proximal colon circular muscles. VIP (0.1 microM) decreased basal slow wave frequency but had no effect on amplitude or duration. When slow waves were enhanced with Bay K 8644 (1 microM), VIP decreased slow wave duration and inhibited contractions. 3. VIP inhibited slow waves and phasic contractions stimulated by tetraethylammonium chloride (TEA; 10 mM), but did not significantly reduce events stimulated by 4-amino-pyridine (4-AP; 10 mM). 4. Whole-cell outward currents were recorded from isolated myocytes, using the amphotericin B perforated patch technique. VIP (1 microM) increased charybdotoxin-insensitive outward currents. 5. Single voltage-dependent K+ channels were recorded in cell-attached patches. VIP increased reversibly the open probability, mean open time and mean burst duration of 4-AP-sensitive, charybdotoxin-insensitive K+ channels (KDR1). Two additional 4-AP- and charybdotoxin-insensitive K+ channels (approximately 90 pS and < 4 pS) were also observed in these patches, but were not significantly affected by VIP. 6. In summary, the effects of VIP on electrical slow waves may be due, in part, to activation of 4-AP-sensitive, 'delayed rectifier' K+ channels. Activation of these channels may contribute to premature slow wave repolarization, reduced Ca2+ entry, and inhibition of contractile force.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2001

Characterization of a delayed rectifier potassium channel in the slowly adapting stretch receptor neuron of crayfish.

Single channel recordings were performed on enzyme-cleaned slowly adapting sensory neurons of crayfish, in cell-attached configuration, with a physiological K(+) gradient across the neuronal membrane. An outward rectifying, voltage-gated K(+) channel with a slope conductance of 13 pS and a K(+) ion permeability of P(K)=6.5 x 10(-14) cm(3)/s was characterized. This 13 pS K(+) channel started to be activated at around 20 mV depolarization. Its open probability increased upon depolarization with V(0.5)= -25.3 mV and P(max)=0.83. The averaged currents showed a delay following the onset of depolarization. The activation time constant was voltage-dependent. The maximal value was 17.0 ms at -25 mV and at +35 mV the time constant was 1.7 ms. Little inactivation was observed throughout the 80- or 1500-ms long depolarization pulses. A sum of two exponentials provided the optimal fit for open time and closed time distribution. At 80-mV depolarization, the open time constants were 0.4 and 10.4 ms; the close time constants were 0.4 and 2.3 ms. The first-latency distribution suggested that at least two closed states preceded two open states. This 13 pS delayed rectifier plays a minor role in the maintenance of the resting membrane potential but contributes to the action potential repolarization. It may also modify the stretch-induced receptor potential and affect the adaptation behaviours in this neuron.

Action Potentials↗
PubMed1994

A delayed rectifier potassium channel cloned from bovine adrenal medulla. Functional analysis after expression in Xenopus oocytes and in a neuroblastoma cell line.

Using a cDNA library from bovine adrenal medulla, and, subsequently, a bovine genomic library, we have isolated the gene coding for a non inactivating potassium channel. This gene encodes a 597-amino acid protein which we have called BAK5 as its sequence is very similar to members of Kv1.5 potassium channel family. Neuroblastoma cells (Neuro-2a cell line) were stably transfected with BAK5 DNA. Protein expression was under the control of a heat-shock promoter. Transfected cells showed a current highly selective for potassium, insensitive to tetraethylammonium but reversibly blocked by 4-aminopyridine. Oocytes injected with BAK5 mRNA also expressed a potassium current with the same characteristics.

4-Aminopyridine↗
PubMed1997

Mitosis-promoting factor-mediated suppression of a cloned delayed rectifier potassium channel expressed in Xenopus oocytes.

The cell cycle is the crucial process that leads to mitosis in all cell types. The dramatic redirectioning of many cellular processes during the cycle is known to involve ion channels, either changing their level of expression or their voltage dependence, as in the case of inward rectifiers. Here we describe the specific inhibition of heterologously expressed ionic channels at the onset of maturation in Xenopus oocytes. In cells expressing rat eag (R-eag) potassium channels, maturation induces a dramatic reduction in the current amplitude, which is almost complete in most cases. The key molecule in oocyte maturation, the mitosis-promoting factor (a complex of cyclin B and p34cdc2), is able to induce similar changes when injected into the oocytes.

Animals↗
PubMed1996

Expression of Kv1.1 delayed rectifier potassium channels in Lec mutant Chinese hamster ovary cell lines reveals a role for sialidation in channel function.

Kv1.1 potassium (K+) channels contain significant amounts of negatively charged sialic acids. To examine the role of sialidation in K+ channel function, Chinese hamster ovary cell lines deficient in glycosylation (Lec mutants) were transfected with rat brain Kv1.1 cDNA. The K+ channel was functionally expressed in all cell lines, but the voltage dependence of activation (V1/2) was shifted to more positive voltages and the activation kinetics were slower in the mutant cell lines compared with control. A similar positive shift in V1/2 was recorded in control cells expressing Kv1.1 following treatment with sialidase or by raising extracellular Ca2+. In contrast, these treatments had little or no effect on the Lec mutants, which indicates that channel sialic acids appear to be the negative surface charges sensitive to Ca2+. The data suggest that sialic acid addition modifies Kv1.1 channel function, possibly by influencing the local electric field detected by its voltage sensor, but that these carbohydrates are not required for cell surface expression.

Animals↗
PubMed1999

Biophysical properties and molecular basis of cardiac rapid and slow delayed rectifier potassium channels.

Normal cardiac action potential repolarization is dependent on activation of several K(+) currents, including I(Kr) and I(Ks). I(Kr) activates rapidly at positive potentials, exhibits inward rectification caused by C-type inactivation, and is potently blocked by methanesulfon-anilide antiarrhythmic drugs and several other common medications. I(Ks) activates very slowly, does not inactivate and is blocked by some benzodiazepines and a chromanol. HERG encodes subunits that form channels that mediate I(Kr). KVLQT1 and minK encode subunits that coassemble to form channels that mediate I(Ks). Mutations in any of these genes cause long QT syndrome, a disorder of cardiac repolarization that predisposes individuals to lethal arrhythmias. In this review, we summarize recent studies of the biophysical and pharmacological properties of HERG and KvLQT1/minK K(+) channels.

Animals↗
PubMed1995

Suppression of two cloned smooth muscle-derived delayed rectifier potassium channels by cholinergic agonists and phorbol esters.

Functional coupling between muscarinic (m3) receptors and two voltage-gated K+ (Kv) channels (Kv1.2 and Kv1.5) cloned originally from canine colonic smooth muscle was studied using the Xenopus oocytes expression system and a mammalian cell line (COS cells). Oocytes were coinjected with cRNAs encoding the human m3 receptor and the Kv channel clones. COS cells were stably transfected with the hm3 cDNA and the cDNA encoding Kv1.5 channels. In oocytes coexpressing hm3 receptors and Kv channels, acetylcholine (ACh, 100 microM) decreased the whole-oocyte Kv channel current (IKv) by 72% over 20 min. ACh was equally effective at suppressing IKv1.2 as IKv1.5. In oocytes expressing only Kv channels phorbol esters (phorboldibutyrate) and phorbol dideconoate (10-30 nM) mimicked the action of ACh on IKv in oocytes coexpressing hm3 receptors. At the single-channel level, both ACh and phorbol dibutyrate applied to the extra-patch membrane reduced the open probability of Kv channels in the cell-attached patches without affecting single-channel conductance. In cotransfected COS cells, over a similar time course as in oocytes ACh suppressed whole-cell IKv1.5, but only by 30% and the effect was not reversible. These data indicate that stimulation of m3 receptors in cells that express Kv1.2 and Kv1.5 channels causes a poorly reversible decrease in the open probability of these channels.

Acetylcholine↗
PubMedDate not supplied

[The nootropic agent vinpocetine blocks the delayed rectifier potassium channel more strongly than the high-conductance calcium channel].

In isolated neurons of Helix snail high-threshold Ca(2+)- and K(+)-currents were recorded using two-microelectrode voltage clamp technique. Extracellular application of nootropic drug vinpocetine rapidly and reversibly blocked both types of current. Vinpocetine effects were dose-dependent and voltage-independent. The maximal effect of Ca(2+)-current blockade was 27% during application of vinpocetine in the concentration of 600 mcM. The maximal blockade of K(+)-current was 75% when the drug was applied in the concentration of 30 mcM. Results suggest that K(+)-channels are more probable targets for vinpocetine than Ca(2+)-channels.

Animals↗
PubMed2005

[Inhibition of salicylate on potassium channels in rat inferior colliculus neurons].

OBJECTIVE: To understand what role of the transient outward potassium channels and the delayed rectifier potassium channels play in the mechanism of salicylate-induced tinnitus. METHODS: The effects of salicylate on the transient outward potassium channels and the delayed rectifier potassium channels in freshly dissociated inferior colliculus neurons of rats were studied, using the whole-cell voltage clamp method. RESULTS: Salicylate blocked the transient outward potassium current (I(K(A and the delayed rectifier potassium current (I(K(DR in concentration-dependent manner (0.1-1 mmol/L). The IC50 values for the blocking action of salicylate on I(K(A)) and I(K(DR)) were 2.27 and 0.80 mmol/L, respectively. At a concentration of 1 mmol/L, salicylate did not shift the activation and inactivation curves of I(K(A)), but significantly shifted the activation and inactivation curves of I(K(DR)) negatively by approximately 11 mV and 24 mV. CONCLUSIONS: Salicylate inhibits both I(K(A)) and I(K(DR)) in rat inferior colliculus neurons but only significantly affects the activation and inactivation kinetics of I(K(DR)). Effects of I(K(A)) and I(K(DR)), especially I(K(DR)), by salicylate may play an important role in salicylate-induced tinnitus.

Animals↗
PubMed2003

Blockers of the slowly delayed rectifier potassium IKs channel: potential antiarrhythmic agents.

Prolongation of the cardiac action potential and the effective refractory period is a proven principle to prevent cardiac arrhythmias, especially under conditions when the action potential is shortened. Several approaches have been made to achieve this effect selectively and without proarrhythmic side effects. Besides the blockade of the cardiac sodium channel, blockade of the delayed rectifier potassium channel I(K) was attempted to achieve this goal. After the discovery that the delayed rectifier potassium channel I(K) consists of two distinct channels, the rapidly and the slowly delayed rectifier potassium channel I(Kr) and I(Ks) respectively, blockers for these targets were looked for. But most of the described blockers of I(K), like dofetilide and D-sotalol, are highly selective and potent I(Kr) channel blockers or have only a side-activity on the I(Ks) channel, as described for azimilide. These compounds have shown their efficacy in terminating atrial or ventricular fibrillation under certain circumstances, but they also have shown high risk to induce arrhythmias by themselves. It was speculated that I(Ks) channel blockers may be free of this unwanted effect and several companies put effort to find compounds selective for this novel target. The strategies to find potent and selective I(Ks) channel will be reviewed as well as their first results in in-vitro and in-vivo models of arrhythmia. As side effects are a potential danger for this ubiquitous channel, also the safety studies with these compounds will be summarized.

Action Potentials↗