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Results for “Delayed Rectifier Potassium Channels”

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PubMed1993

Contrasting immunohistochemical localizations in rat brain of two novel K+ channels of the Shab subfamily.

We have localized CDRK and DRK1, two novel K+ channels of the Shab subfamily by immunohistochemistry. The two channels are closely related in structure with about 90% amino acid identity in the N-terminal and middle portions and 60% identity in the C-terminal region. We observe striking differences in cellular localizations of the two channels. DRK1 tends to localize to cell bodies and proximal dendrites discretely, while CDRK is diffusely present in cell bodies and is also found on fibers in specific brain areas. In the cerebral cortex DRK1 is localized to pyramidal cells, whereas CDRK occurs in small cells, presumably interneurons. These localizations may reflect specialized delayed rectifier functions and targeting properties manifested differentially by K+ channel subfamily members.

Animals↗
PubMed2005

A gating mutation at the internal mouth of the Kir6.2 pore is associated with DEND syndrome.

Inwardly rectifying potassium (Kir) channels control cell membrane K+ fluxes and electrical signalling in diverse cell types. Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive (K(ATP)) channel, cause permanent neonatal diabetes mellitus. However, the I296L mutation also results in developmental delay, muscle weakness and epilepsy. We investigated the functional effects of the I296L mutation by expressing wild-type or mutant Kir6.2/SUR1 channels in Xenopus oocytes. The mutation caused a marked increase in resting whole-cell K(ATP) currents by reducing channel inhibition by ATP, in both homomeric and simulated heterozygous states. Kinetic analysis showed that the mutation impaired ATP sensitivity indirectly, by stabilizing the open state of the channel and possibly also by means of an allosteric effect on ATP binding and/or transduction. The results implicate a new region in Kir-channel gating and suggest that disease severity is correlated with the extent of reduction in ATP sensitivity.

Adenosine Triphosphate↗
PubMed1990

Lead inhibits the voltage-activated calcium current of Aplysia neurons.

Lead is a potent and reversible inhibitor of the voltage-dependent calcium current of Aplysia neurons in a concentration range (1-1000 microM) similar to that which elicits toxic effects in man. The threshold for inhibition is 1 microM and the dissociation constant about 90 microM. The inhibition is due to reduction of the peak current amplitude, and not due to alteration of the voltage dependence of the activation or inactivation. The effect of lead is specific to the calcium current as the delayed rectifier potassium and the sodium currents are not affected by concentrations of lead (200 microM) which give near-maximal inhibition. The calcium current of Aplysia neurons appears similar to the current flowing through the mammalian L-type calcium channel. This suggests that inhibition of the investigated calcium channel may contribute to the toxic effects of lead in mammals.

Animals↗
PubMed1999

Inactivation gating and 4-AP sensitivity in human brain Kv1.4 potassium channel.

Voltage-gated K(+) channels vary in sensitivity to block by 4-aminopyridine (4-AP) over a 1000-fold range. Most K(+) channel phenotypes with leucine at the fourth position (L4) in the leucine heptad repeat region, spanning the S4-S5 linker, exhibit low 4-AP sensitivity, while channels with phenylalanine exhibit high sensitivity. Mutational analysis on delayed rectifier type K(+) channels demonstrate increased 4-AP sensitivity upon mutation of the L4 heptad leucine to phenylalanine. This mutation can also influence inactivation gating, which is known to compete with 4-AP in rapidly inactivating A-type K(+) channels. Here, in a rapidly inactivating human brain Kv1.4 channel, we demonstrate a 400-fold increase in 4-AP sensitivity following substitution of L4 with phenylalanine. Accompanying this mutation is a slowing of inactivation, an acceleration of deactivation, and depolarizing shifts in the voltage dependence of activation and steady-state inactivation. To test the relative role of fast inactivation in modulating 4-AP block, N-terminal deletions of the fast inactivation gate were carried out in both channels. These deletions produced no change in 4-AP sensitivity in the mutant channel and approximately a six-fold increase in the wild type channel. These results support the view that changes at L4 which increase 4-AP sensitivity are largely due to 4-AP binding and may, in part, arise from alterations in channel conformation. Primarily, this study demonstrates that the fast inactivation gate is not a critical determinant of 4-AP sensitivity in Kv1.4 channels.

4-Aminopyridine↗
PubMed2001

Ceramide inhibits the outward potassium current in rat pinealocytes.

In the present study, we investigated the effect of ceramide on the outward K(+) current in rat pinealocytes using whole cell and single channel recordings. Three components of the whole cell outward K(+) current were separated, an iberiotoxin (IBTX)-sensitive K(+) current (I(KCa)), a transient A current (I(A)) and a delayed rectifier current (I(K)). C6-ceramide reduced all three components of the outward K(+) current. C6-ceramide (30 microM) caused a 53% inhibition of I(KCa) [a component that is generated by the IBTX-sensitive K(+) channel (BK channel)], a 27% inhibition of I(A) and a 17% inhibition of I(K). Additional studies showed that the BK channel was not inhibited by dihydroC6-ceramide, the inactive analog of C6-ceramide, but mimicked by sphingomyelinase which increased intracellular ceramide. The ceramide inhibition of the BK channel was only partly dependent on its inhibition of the L-type Ca(2+) channel. Studies using specific kinase inhibitors showed that calphostin C (a protein kinase C inhibitor) and to a lesser degree lavendustin A (a tyrosine kinase inhibitor) were effective in reducing the ceramide inhibition of I(KCa). Taken together, our results show that, in rat pinealocytes, ceramide reduces the outward K(+) current predominantly by inhibiting I(KCa). Moreover, protein kinase C appears to be the main kinase involved in the ceramide inhibition of I(KCa).

Animals↗
PubMed2006

[Electrophysiological study on rat conduit pulmonary artery smooth muscle cells under normoxia and acute hypoxia].

The present study was designed to investigate the electrophysiological characteristics of rat conduit pulmonary artery smooth muscle cells (PASMCs) and the response to acute hypoxia. PASMCs of the 1st to 2nd order branches in the conduit pulmonary arteries were obtained by enzymatic isolation. The PASMCs were divided into acute hypoxia preconditioned group and normoxia group. Hypoxia solutions were achieved by bubbling with 5% CO2 plus 95% N2 for at least 30 min before cell perfusion. Potassium currents were compared between these two groups using whole-cell patch clamp technique. The total outward current of PASMCs was measured under normoxia condition when iBTX [specific blocking agent of large conductance Ca-activated K(+) (BK(Ca)) channel] and 4-AP [specific blocking agent of delayed rectifier K(+) (K(DR)) channel] were added consequently into bath solution. PASMCs were classified into three types according to their size, shape and electrophysiological characteristics. Type I cells are the smallest with spindle shape, smooth surface and discrete perinuclear bulge. Type II cells show the biggest size with banana-like appearance. Type III cells have the similar size with type I, and present intermediary shape between type I and type II. iBTX had little effect on the total outward current in type I cells, while 4-AP almost completely blocked it. Most of the total outward current in type II cells was inhibited by iBTX, and the remaining was sensitive to 4-AP. In type III cells, the total outward current was sensitive to both iBTX and 4-AP. Acute hypoxia reduced the current in all three types of cells: (1614.8+/-62.5) pA to (892.4+/-33.6) pA for type I cells (P<0.01); (438.3+/-42.8) pA to (277.5+/-44.7) pA for type II cells (P<0.01); (1 042.0+/-37.2) pA to (613.6+/-23.8) pA for type III (P<0.01), and raised the resting membrane potentials (E(m)) in all these three types of cells: (-41.6+/-1.6) mV to (-18.6+/-1.5) mV (P<0.01), (-42.3+/-3.8) mV to (-30.6+/-3.0) mV (P<0.01), (-43.3+/-1.6) mV to (-28.4+/-1.4) mV (P<0.01), for type I, II, III cells, respectively. These results suggest that acute hypoxia suppresses the potassium current and improves the E(m) in PASMCs. These effects may be involved in the modulation of constriction/relaxation of conduit artery under acute hypoxia. Different distribution of K(DR) and BK(Ca) channels in these three types of PASMCs might account for their different constriction/relaxation response to acute hypoxia.

4-Aminopyridine↗
PubMed1998

Inhibition of voltage-gated cationic channels in rat embryonic hypothalamic neurones and C1300 neuroblastoma cells by triphenylethylene antioestrogens.

The effect of the non-steroidal antioestrogens tamoxifen and toremifene on voltage-gated cationic currents was examined in primary cultures of rat hypothalamic neurones and the C1300 mouse neuroblastoma cell line using the whole-cell patch clamp technique. When applied to the external bathing solution both tamoxifen and toremifene were able to inhibit TTX-sensitive sodium currents with IC50 values of 1-2 microM and delayed rectifier type potassium currents (IC50, 2-3 microM). However, only toremifene showed a significant inhibition of the I(A) current (IC50 3 microM). Inhibition of voltage-gated cationic currents was significantly impaired when tamoxifen was applied in a serum-containing solution. The steroidal antioestrogen ICI 182,780 did not inhibit any of the currents at 10 microM.

Animals↗
PubMed1994

Molecular basis of cardiac potassium channel stimulation by protein kinase A.

Cardiac beta-adrenergic receptors accelerate heart rate by modulating ionic currents through a pathway involving cyclic AMP-dependent protein kinase A (PKA). Previous studies have focused on the regulation of Ca2+ channels by PKA; however, due to the heterogeneity of K+ channels expressed within the heart, little is known about the mechanism by which PKA modulates individual K+ channels. Here we report that PKA strongly enhanced the activity of a cloned delayed rectifier K+ channel that is normally expressed in cardiac atria. This effect required a single PKA consensus phosphorylation site located near the amino terminus of the channel protein. Furthermore, patch clamp analysis revealed that PKA phosphorylation increased the open time that single channels spend in higher conductance states. These studies provide evidence that hormonal modulation of a cardiac K+ channel involves direct phosphorylation by PKA.

Amino Acid Sequence↗
PubMed1992

Potassium rectifier currents differ in myocytes of endocardial and epicardial origin.

Whole-cell voltage-clamp experiments and single-channel current recordings in cell-attached patch mode were performed on enzymatically dissociated single ventricular myocytes harvested from feline endocardial and epicardial surfaces. The studies were designed to compare the characteristics of inward rectifier K+ current (IK1) and delayed rectifier K+ current (IK) between endocardial and epicardial cells and to test the hypothesis that the differential characteristics of IK1 and/or IK are responsible for the differences in action potential configuration between the two cell types. IK1 in endocardial cells displayed a distinct N-shaped current-voltage (I-V) relation, with a prominent outward current at potentials between -80 and -30 mV. In epicardial cells, an outward current region was much smaller, and the I-V relation demonstrated a blunted N-shaped I-V relation. In single-channel current recordings in cell-attached patch mode, neither unitary current amplitude of IK1 nor probability of channel opening was different between endocardial and epicardial cells, suggesting that the difference in the number of functional channels might be responsible for the differential IK1 I-V relations. The characteristics of IK also differed between endocardial and epicardial cells. The time course of growth of tail current of IK (IK,tail) (activation of IK) was significantly enhanced and that of IK,tail deactivation was delayed in epicardial cells compared with endocardial cells. The time constant of the slow component of IK activation at +20 mV was 3,950 +/- 787 msec in endocardial cells and 2,746 +/- 689 msec in epicardial cells (p less than 0.05); the corresponding values for IK deactivation at -50 mV were 1,041 +/- 387 msec and 1,959 +/- 551 msec, respectively (p less than 0.01). The voltage dependence of steady-state activation of IK,tail was similar between endocardial and epicardial cells, suggesting that the probability of channel opening at any potential was not different in the two cell types. The amplitude and density of fully activated IK (IK,full) were significantly greater in epicardial cells than in endocardial cells. At repolarization to -20 mV, IK,full amplitude was 452 +/- 113 pA in endocardial cells and 578 +/- 135 pA in epicardial cells (p less than 0.05), and the corresponding values for IK,full density were 2.86 +/- 0.73 and 4.21 +/- 0.83 microA/cm2, respectively (p less than 0.05). A nonstationary fluctuation analysis revealed that the amplitude of IK unitary current was similar between endocardial and epicardial cells (0.23 +/- 0.07 versus 0.22 +/- 0.03 pA, p = NS).(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1996

K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current.

In mammalian cardiac cells, a variety of transient or sustained K+ currents contribute to the repolarization of action potentials. There are two main components of the delayed-rectifier sustained K+ current, I(Kr) (rapid) and I(Ks), (slow). I(Kr) is the product of the gene HERG, which is altered in the long-QT syndrome, LQT2. A channel with properties similar to those of the I(Ks) channel is produced when the cardiac protein IsK is expressed in Xenopus oocytes. However, it is a small protein with a very unusual structure for a cation channel. The LQT1 gene is another gene associated with the LQT syndrome, a disorder that causes sudden death from ventricular arrhythmias. Here we report the cloning of the full-length mouse K(V)LQT1 complementary DNA and show that K(V)LQT1 associates with IsK to form the channel underlying the I(Ks) cardiac current, which is a target of class-III anti-arrhythmic drugs and is involved in the LQT1 syndrome.

Amino Acid Sequence↗
PubMed1995

Propafenone preferentially blocks the rapidly activating component of delayed rectifier K+ current in guinea pig ventricular myocytes. Voltage-independent and time-dependent block of the slowly activating component.

The effects of propafenone on the delayed rectifier K+ current were studied in guinea pig ventricular myocytes by using the patch-clamp technique. In these myocytes, this current consists of at least two components: a La(3+)-sensitive component activating rapidly with moderate depolarizations and a La(3+)-resistant current slowly activating at more positive potentials. In the absence of La3+ (when both components are present), propafenone inhibited the delayed outward current, its effects being more marked after weak than after strong depolarizations. Propafenone-induced block of the tail currents elicited on return to -30 mV was more marked after short than after long depolarizing pulses. In the presence of 1 mumol/L propafenone, the envelope-of-tails test was satisfied, thus indicating that at this concentration propafenone completely blocks the rapidly activating component. In the presence of La3+ (when only the slow component is present), the steady state inhibition induced by 5 mumol/L propafenone on both the maximum activated and the tail currents was independent of the test pulse voltage. Development of propafenone-induced block on the slowly activating component was very fast and linked to channel opening. In addition, the blockade appeared to be use dependent, with the rate constant of the onset kinetics at 2 Hz being 0.44 +/- 0.1 pulse-1. The recovery process from propafenone-induced block exhibited a time constant of 2.5 +/- 0.4 s. These results indicated that propafenone preferentially inhibits the rapidly activating component of the delayed rectifier and that it blocks in a voltage-independent and time-dependent manner the slow component of this current.

Animals↗
PubMed1996

Synergistic action of NS-004 and internal Ca2+ concentration in modulating pulmonary artery K+ channels.

Considering the singular vasomotor behavior of the pulmonary artery, we were interested to test NS-004 (1-(2'-hydroxy-5'-chlorophenyl)-5-trifluoromethyl-2(3H)-benzimidazolo ne) on pulmonary artery smooth muscle cells. Using the patch clamp technique, we identified a delayed rectifier K+ current and a Ca(2+)-activated K+ current. With a low free intracellular Ca2+ concentration ([Ca2+]i), 10-50 microM NS-004 activated a noisy outward current which was blocked by iberiotoxin. 50 microM NS-004 also inhibited a smooth inactivating outward current. Under these conditions, 10 microM NS-004 induced no change in the resting membrane potential. With a higher free [Ca2+]i, 10 microM NS-004 was 3.5 times more efficacious in increasing the noisy current and it induced a hyperpolarization. We concluded that increasing free [Ca2+]i induced potentiation of the NS-004-induced activation of high conductance Ca(2+)-sensitive K+ channels and of the NS-004-induced hyperpolarization of the cell. The delayed rectifier K+ channel was inhibited by NS-004 as well as by an increased free [Ca2+]i.

4-Aminopyridine↗
PubMed2005

Selective inhibition of pinacidil effects by estrogen in guinea pig heart.

BACKGROUND: Recently, gender related differences in heart function have been extensively studied. Some of them, as differences in repolarization between males and females have been explained by direct effect of estrogen on delayed rectifier K+ channels and Ca2+ channels. It seems that estrogen induces overexpression of SUR2A subunits of ATP-sensitive K+ channels. The aim of this paper was to compare heart rate changes in male and female guinea pigs in the presence of different potassium channel openers (PCOs). METHODS: We used spontaneously beating right atria from control and estrogen receptor modulator-treated male and female guinea pigs (17-beta-estradiol as a stimulator and tamoxifen as a blocker of estrogen receptor located in heart muscle). RESULTS: In control females, rilmakalim and diazoxide, but not pinacidil elicited concentration-dependent decrease of heart rate. On the other hand, all three PCOs induced similar negative chronotropic action in hearts obtained from male control group (Emax was between -40 and -70 bpm, respectively). After two weeks of treatment with 17-beta-estradiol, pinacidil failed to significantly decrease heart rate in males however, tamoxifen-pretreated female group responded by decrease in automatism in the presence of rising concentration of pinacidil (Emax=-45+/-6 bpm, not significantly different from Emax in male control=-40+/-5 bpm, n=7). Interestingly, we observed lower blood concentration of the heart form of lactate dehydrogenase (H-LDH) in female than in male control group. Moreover, H-LDH concentration increased in tamoxifen-pretreated female group and decreased in 17-beta-estradiol-treated male group. CONCLUSION: Our results indicate that estrogen downregulates H-LDH production and specifically modulate pinacidil action in guinea pig right atria, probably by changes of binding site for this drug in SUR2A receptor, but not for rilmakalim and diazoxide.

Animals↗
PubMed2003

Differential effects of lidocaine and tramadol on modified nerve impulse by 4-aminopyridine in rats.

We have used the sucrose gap method to measure the effects of drugs on the electrophysiological properties of rat sciatic nerves. The results showed that 4-aminopyridine produced a slight conduction block, prolonged the duration of action potential, enhanced the hyperpolarizing afterpotential, and elicited a hump that followed the action potential. In the presence of 4-aminopyridine, the impulse-blocking activity of lidocaine and tramadol was enhanced. Both lidocaine and tramadol effectively depressed the delayed depolarization generated by 4-aminopyridine. While tramadol decreased the activity-evoked hyperpolarizing afterpotentials, lidocaine completely removed them. These findings indicate that lidocaine may be more effective in blocking the Na(+) channels than tramadol. Tramadol may be more effective on the delayed rectifier K(+) channels than lidocaine.

4-Aminopyridine↗
PubMed1992

Potassium currents of rat basilar artery smooth muscle cells.

Primary isolates of smooth muscle cells from the basilar artery of the rat were studied using whole-cell and single-channel patch-clamp techniques. Two distinct potassium currents were characterized. With low intracellular calcium, depolarization above 0 mV elicited an outward current of a few hundred pA (at +120 mV) with sigmoidal onset and little inactivation during 1.25 s steps. This current was reduced by bath application of 1 mM procaine or 1 mM strychnine, but not by 500 nM charybdotoxin. These are characteristics of the delayed rectifier potassium current in other preparations. With higher intracellular calcium, depolarization above 0 mV elicited a non-inactivating potassium current of several nA (at +120 mV). This current persisted in the presence of 1 mM procaine or strychnine but was reduced by bath application of 100 nM charybdotoxin. In whole-cell recordings in which intracellular calcium was unbuffered with EGTA, spontaneous transient outward currents were manifest and displayed voltage dependence and tail currents similar to the calcium-dependent current. The spontaneous transient current and the calcium-dependent current had similar sensitivity to charybdotoxin. Cell-free membrane patches contained one or more channels of 220 pS (in solutions symmetrical with respect to potassium) with similar voltage and calcium dependence. These are characteristics of the large conductance calcium-activated potassium current in other preparations.

Animals↗
PubMed1995

The selectivity of different external binding sites for quaternary ammonium ions in cloned potassium channels.

Tetraethylammonium (TEA) is thought to be the most effective quaternary ammonium (QA) ion blocker at the external site of K+ channels, and small changes to the TEA ion reduce its potency. To examine the properties of the external QA receptor, we applied a variety of QA ions to excised patches from human embryonic kidney cells or Xenopus oocytes transfected with the delayed rectifying K+ channels Kv 2.1 and Kv 3.1. In outside-out patches of Kv 3.1, the relative potencies were TEA > tetrapropylammonium (TPA) > tetrabutylammonium (TBA). In contrast to Kv 3.1, the relative potencies in Kv 2.1 were TBA > TEA > TPA. In Kv 3.1 and Kv 2.1, external tetrapentylammonium (TPeA) blocked K+ currents in a fast, reversible and, in contrast to TEA, time-dependent manner. The external binding of TPeA appeared to be voltage independent, unlike the effects of TPeA applied to inside-out patches. External n-alkyl-triethylammonium compounds (C8, C10 chain length) had a lower affinity than TEA in Kv 3.1, but a higher affinity than TEA in Kv 2.1. In Kv 3.1, the decrease in QA affinity was large when one or two methyl groups were substituted for ethyl groups in TEA, but minor when propyl groups replaced ethyl groups. Changes in the free energy of binding could be correlated to changes in the free energy of hydration of TEA derivatives calculated by continuum methodology. These results reveal a substantial hydrophobic component of external QA ion binding to Kv 2.1, and to a lesser degree to Kv 3.1, in addition to the generally accepted electrostatic interactions. The chain length of hydrophobic TEA derivatives affects the affinity for the hydrophobic binding site, whereas the hydropathy of QA ions determines the electrostatic interaction energy.

Animals↗
PubMed2003

Implementation of a fast 16-Bit dynamic clamp using LabVIEW-RT.

The dynamic-clamp method provides a powerful electrophysiological tool for creating virtual ionic conductances in living cells and studying their influence on membrane potential. Here we describe G-clamp, a new way to implement a dynamic clamp using the real-time version of the Lab-VIEW programming environment together with a Windows host, an embedded microprocessor that runs a real-time operating system and a multifunction data-acquisition board. The software includes descriptions of a fast voltage-dependent sodium conductance, delayed rectifier, M-type and A-type potassium conductances, and a leak conductance. The system can also read synaptic conductance waveforms from preassembled data files. These virtual conductances can be reliably implemented at speeds < or =43 kHz while simultaneously saving two channels of data with 16-bit precision. G-clamp also includes utilities for measuring current-voltage relations, synaptic strength, and synaptic gain. Taking an approach built on a commercially available software/hardware platform has resulted in a system that is easy to assemble and upgrade. In addition, the graphical programming structure of LabVIEW should make it relatively easy for others to adapt G-clamp for new experimental applications.

Analog-Digital Conversion↗
PubMed1995

Changes in pharyngeal respiratory muscle force produced by K+ channel blockade.

The purpose of the present study was to determine whether the contractility of pharyngeal respiratory muscles can be augmented by altering membranous K+ channel conductance. The effects on twitch force of two K+ channel blockers, tetraethylammonium (TEA, 10 mM) and 4-aminopyridine (4-AP, 0.3 mM), were examined in vitro for sternohyoid and diaphragm muscle strips. Both agents augmented isometric twitch force of both muscles. In response to TEA twitch force of the sternohyoid muscle increased significantly more than that of the diaphragm (by 33 +/- 7 vs. 9 +/- 1%, P = 0.004), whereas with 4-AP the increase in twitch force of the sternohyoid muscle was comparable to that of the diaphragm (55 +/- 15 vs. 64 +/- 6%, P = 0.50). 4-AP shifted the force-frequency relationship of both muscles leftward but did not alter peak tetanic force, so that force with 4-AP exceeded that without drug at stimulation frequencies below 60 Hz. In contrast TEA reduced force at stimulation frequencies > 20 Hz. The isometric contraction times of both muscles was variably prolonged, more so with 4-AP (by 30 +/- 15% for the sternohyoid and 32 +/- 3% for the diaphragm) than with TEA (by 9 +/- 2% for the sternohyoid and 5 +/- 2% for the diaphragm). For the group of muscles and K+ channel blockers, the degree of augmentation of twitch force correlated with the degree of prolongation of contraction time (r = 0.82, P < 0.001), consistent with blocking delayed rectifier K+ channels as the mechanism of increasing muscle force.

4-Aminopyridine↗