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PubMed2000

A function of delayed rectifier potassium channels in glial cells: maintenance of an auxiliary membrane potential under pathological conditions.

Müller glial cells from human and guinea-pig retinae were investigated using the whole-cell patch-clamp technique. Human Müller cells from eyes with different diseases were characterized by diminished inwardly-rectifying K(+) currents. A comparable reduction of these currents was achieved in guinea pig Müller cells by treatment with iodoacetate to generate ischemia-like conditions. Consequently, the membrane potentials were reduced significantly in both diseased human and iodoacetate-treated guinea-pig Müller cells as compared to normal controls. However, the potentials were still clearly negative. Delayed rectifier currents could still be recorded under these conditions. Application of quinine blocked the delayed rectifier K(+) channels, and resulted in a total breakdown of the membrane potentials. Thus, it becomes apparent that the glial delayed rectifier K(+) channels are necessary to maintain an 'auxiliary' membrane potential under certain pathological conditions that are characterized by an almost total loss of inward rectifier conductance. Therefore, the delayed rectifier K(+) channels of glial cells may become crucial for the support of basic glial functions.

Adenosine Triphosphate↗
PubMed1993

Delayed rectifier potassium channels in ventricle and sinoatrial node of the guinea pig: molecular and regulatory properties.

We focus on the regulatory properties of delayed rectifier K+ (IK) channels in guinea-pig sinoatrial node (SAN) and compare SAN IK to the better characterized ventricular IK. Despite demonstrated similarities in the properties of IK in guinea-pig ventricle and SAN, the possibility remains that expression of IK channels can vary regionally within the same heart. Like ventricular IK, SAN IK can be enhanced by beta-adrenergic stimulation and exposure to phorbol ester. However, in contrast to ventricular IK, regulation of SAN IK by protein kinases A and C is not temperature dependent. Basal SAN IK can be diminished by muscarinic agonists, while beta-adrenergic stimulation is a precondition for reduction of ventricular IK by cholinergic agonists. Nonstationary state fluctuation analysis predicts a small single-channel current (1 pA) and a large number of functional channels (308) associated with whole-cell SAN IK. The corresponding single-channel conductance of 6 pS is somewhat larger than that estimated for ventricular IK. Overall comparisons of guinea-pig ventricular and SAN IK to the current associated with the minK channel clone suggest that the native guinea-pig cardiac IK channels may be related not only to each other but lso to the minK channel protein.

Animals↗
PubMed2002

Delayed rectifier potassium channels contribute to the depressed pulmonary artery contractility in pneumonia.

We investigated the role of K(+) channels in the attenuated pulmonary artery (PA) contractility characteristic of acute Pseudomonas pneumonia. Contractility of PA rings from the lungs of control or pneumonia rats was assessed in vitro by obtaining cumulative concentration-response curves to the contractile agonists KCl, phenylephrine, or PGF(2 alpha) on PA rings before and after treatment with K(+) channel blockers. In rings from pneumonia rats, paxilline (10 microM), tetraethylammonium (2 mM) (blockers of large-conductance Ca(2+)-activated K(+) channels), and glybenclamide (ATP-sensitive K(+) channel blocker, 80 microM) had no significant effect on the attenuated contractile responses to KCl, phenylephrine, and PGF(2 alpha). However, 4-aminopyridine (2 mM), a blocker of voltage-gated K(+) channels (delayed rectifier K(+) channel) reversed this depressed contractility. Therefore, large-conductance Ca(2+)-activated K(+) and ATP-sensitive K(+) channels do not contribute to the attenuated PA contractility observed in this model of acute pneumonia. In contrast, 4-aminopyridine enhances contraction in PA rings from pneumonia lungs, consistent with involvement of a voltage-gated K(+) channel in the depressed PA contractility in acute pneumonia. Unraveling the precise mechanism of attenuated contractility in pneumonia could lead to innovative therapies for the pulmonary vascular abnormalities associated with this disease.

Adenosine Triphosphate↗
PubMed2001

Molecular cloning and functional characterization of a novel delayed rectifier potassium channel from channel catfish (Ictalurus punctatus): expression in taste buds.

The gustatory system of channel catfish is widely studied for its sensitivity to amino acids. As a first step in identifying the molecular components that play a role in taste transduction in catfish, we cloned the full-length cDNA for Kv2-catfish, a novel K(+) channel that is expressed in taste buds. The deduced amino acid sequence is 816 residues, and shares a 56-59% sequence identity with Kv2.1 and Kv2.2, the other members of the vertebrate Kv2 subfamily of voltage-gated K(+) channels. The Kv2-catfish RNA was expressed in taste buds, brain, skeletal muscle, kidney, intestine and gills, and its gene is represented as a single copy in the catfish genome. Recombinant channels expressed in Xenopus oocytes were selective for K(+), and were inhibited by tetraethylammonium applied to the extracellular side of the membrane during two-electrode voltage clamp analysis with a 50% inhibitory constant of 6.1 mM. The channels showed voltage-dependent activation, and did not inactivate within 200 ms. Functionally, Kv2-catfish is a voltage-gated, delayed rectifier K(+) channel, and its primary structure is the most divergent sequence identified among the vertebrate members of the Kv2 subfamily of K(+) channels, being related equally well to Kv2.1 and Kv2.2.

Amino Acid Sequence↗
PubMed1992

Delayed rectifier potassium channels in canine and porcine airway smooth muscle cells.

1. In order to define the ion channels underlying the inactivating, calcium-insensitive current in airway smooth muscle cells, unitary potassium currents were recorded from canine and porcine trachealis cells, and compared with macroscopic currents. On-cell and inside-out single-channel currents were compared with whole-cell recordings made in dialysed cells. 2. Depolarizing voltage steps evoked outward unitary currents. In addition to a large conductance, calcium-activated potassium channel (KCa), a lower conductance potassium channel was identified. This channel has a conductance of 12.7 pS (on-cell; 1 mM-K+ in the pipette). 3. The lower conductance channel (Kdr) was not sensitive to cytosolic Ca2+ concentration and unitary current openings occurred following a delay after the voltage step. The time course of activation of the current composed of averaged single-channel events was very similar to that of the whole-cell, delayed rectifier potassium current (IdK), recorded under conditions of low intracellular calcium (Kotlikoff, 1990). 4. Kdr channels also inactivated with kinetics similar to those of the macroscopic current. Averaged single-channel records revealed a current that inactivated with kinetics that could be described by two exponentials (tau 1 = 0.14 s, tau 2 = 1.1 s; at 5 mV). These values corresponded well with previously determined values for time-dependent inactivation of IdK. Inactivation of Kdr channels was markedly voltage dependent, and was well fitted by a Boltzmann equation with V50 = -53 mV; this was similar to measurements of the macroscopic current, although the V50 value was shifted to more positive potentials in whole-cell measurements. When only the inactivating component of the macroscopic current was considered, the voltage dependence of inactivation of the single-channel current and macroscopic current were quite similar. 5. Single-channel kinetics indicated that Kdr channels occupy one open and two closed states. The mean open time was 1.7 ms. Inactivation results in a prominent increase in the long closed time, with little effect on the mean open time or short closed time. 6. The Kdr channel was not blocked by tetraethylammonium (TEA; 1 mM), charybdotoxin (ChTX; 100 nM) or glibenclamide (20 microM), but was blocked by 4-aminopyridine (4-AP; 1 mM). Similarly, 4-AP blocked the inactivating component of the macroscopic current, but a non-inactivating current remained. KCa currents were blocked by TEA (0.5-1 mM) and charybdotoxin (40 nM), but were insensitive to to 4-AP (1 mM) and glibenclamide (20 microM).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Ion permeation and block of M-type and delayed rectifier potassium channels. Whole-cell recordings from bullfrog sympathetic neurons.

Ion permeation and conduction were studied using whole-cell recordings of the M-current (I(M)) and delayed rectifier (IDR), two K+ currents that differ greatly in kinetics and modulation. Currents were recorded from isolated bullfrog sympathetic neurons with 88 mM [K+]i and various external cations. Selectivity for extracellular monovalent cations was assessed from permeability ratios calculated from reversal potentials and from chord conductances for inward current. PRb/PK was near 1.0 for both channels, and GRb/GK was 0.87 +/- 0.01 for IDR but only 0.35 +/- 0.01 for I(M) (15 mM [Rb+]o or [K+]o). The permeability sequences were generally similar for I(M) and IDR: K+ approximately Rb+ > NH4+ > Cs+, with no measurable permeability to Li+ or CH3NH3+. However, Na+ carried detectable inward current for IDR but not I(M). Nao+ also blocked inward K+ current for IDR (but not IM), at an apparent electrical distance (delta) approximately 0.4, with extrapolated dissociation constant (KD) approximately 1 M at 0 mV. Much of the instantaneous rectification of IDR in physiologic ionic conditions resulted from block by Nao+. Extracellular Cs+ carried detectable inward current for both channel types, and blocked I(M) with higher affinity (KD = 97 mM at 0 mV for I(M), KD) approximately 0.2 M at 0 mV for IDR), with delta approximately 0.9 for both. IDR showed several characteristics reflecting a multi-ion pore, including a small anomalous mole fraction effect for PRb/PK, concentration-dependent GRb/GK, and concentration-dependent apparent KD's and delta's for block by Nao+ and Cso+. I(M) showed no clear evidence of multi-ion pore behavior. For I(M), a two-barrier one-site model could describe permeation of K+ and Rb+ and block by Cso+, whereas for IDR even a three-barrier, two-site model was not fully adequate.

Animals↗
PubMed1988

Changes in densities and kinetics of delayed rectifier potassium channels during neuronal differentiation.

Single-channel K+ currents were recorded from young and mature spinal neurons cultured from Xenopus embryos to examine the bases of the developmental increases in density and in rate of activation of the macroscopic voltage-dependent delayed rectifier K+ current (IKv). K+ channels of three conductance classes (integral of 80, 30, and 15 pS) are present at both ages, but only the intermediate and small conductance classes are voltage-dependent and thus underlie IKv. The increase in the density of IKv is due to increases in the numbers of intermediate and small channels per cell, but not to changes in their open probabilities. The increase in rate of activation of IKv results from a change in the activation kinetics of the intermediate channel class alone.

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↗