Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Delayed Rectifier 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 1,405 records · Page 78Linked to original sources
PubMed1990

Phosphorylation affects voltage gating of the delayed rectifier K+ channel by electrostatic interactions.

The delayed rectifier K+ channel of the squid axon undergoes a series of modifications in its kinetic and conductive parameters when it is phosphorylated as the result of shifts in its voltage-dependent parameters. These effects can be interpreted as due to electrostatic interaction between the voltage sensor of the channel and the transferred phosphate from ATP. Using different concentrations of intracellular Mg2+, we determined the density of surface charges seen by the K+ channel voltage sensor before and after phosphorylation. Values for the surface charge density in the cytoplasmic side of the membrane were between 1/350 and 1/250 e-/A2 in the absence of ATP and between 1/160 and 1/155 e-/A2 under phosphorylating conditions. Incorporation of a surface potential into a kinetic model for the delayed rectifier channel can predict quantitatively phosphorylation-like changes in K+ currents. These results provide evidence for the importance of electrostatic interactions as one of the mechanisms by which phosphorylation modulates the behavior of voltage-dependent channels.

Animals↗
PubMed1987

A patch-clamp study of mammalian platelets and their voltage-gated potassium current.

1. Mammalian platelets were freshly isolated from human, rabbit, or rat blood. The whole-cell and cell-attached voltage-clamp variations of the patch-clamp technique were employed to study the passive electrical properties and ion channels of unstimulated platelets. 2. The input capacitance of a platelet measured by the phase-sensitive detection method was about 128 fF, the input resistance of a platelet was about 59 G omega and the resting membrane potential was about -50 mV which was directly measured by a whole-cell recording in the current-clamp mode. 3. The predominant ion channel was a voltage-gated K+ channel resembling the delayed rectifier K+ channel of nerve, muscle and T-lymphocyte. There was no indication of any inward current in the platelet membrane. The activation of the K+ current could be fitted by n4 kinetics, and was half-maximal at about -35 mV. 4. The time constant of K+ current inactivation was virtually independent of voltage and varied from cell to cell. Recovery from inactivation was slow and dependent on the size and duration of the preceding conditional voltage step. Steady-state inactivation was half-maximal at about -50 mV and was complete at positive potentials. 5. The predominant single-K+-channel conductance was 9 pS and the estimated number of K+ channels per platelet was about 325, corresponding to a density of 25/micron2 apparent membrane area.

Action Potentials↗
PubMed2006

[Molecular pharmacological studies on potassium channels and their regulatory molecules].

K+ channels play important roles in the control of a large variety of physiological functions such as muscle contraction, neurotransmitter release, hormone secretion, and cell proliferation. Over 100 cloned K+ channel pore-forming alpha and accessory beta subunits have been identified so far. Here, we introduce a series of molecular pharmacological and physiological studies on some types of voltage-dependent K+ channels and Ca2+-activated K+ channels. We examined molecular cloning and functional characterization of novel, fast-inactivating, A-type K+ channel alpha (Kv4.3L) and beta (KChIP2S) subunits predominantly expressed in mammalian heart and found the sites in Kv4 channels for 1) the regulation of voltage dependency and 2) the CaMKII phosphorylation in the C-terminal cytoplasmic domain. Moreover, we found that delayed rectifier-type K+ channels (ERG1 and KCNQ) contribute to the resting membrane conductance in vascular and gastrointestinal smooth muscles. The large-conductance Ca2+-activated K+ (BK) channel is ubiquitously expressed and contributes to diverse physiological processes. Recent reports have shown that a BK-like channel (mitoKCa) is expressed in cardiac mitochondria, suggesting that BK channel openers protect mammalian hearts against ischemic injury. Our studies revealed that BKbeta1 interacts with cytochrome c oxidase I (Cco1) in cardiac mitochondria, and that the activation of BK channels by 17beta-estradiol results in a significant increase in the survival rate of ventricular myocytes. These findings suggest that BKbeta1 may play an important role in the regulation of cell respiration in cardiac myocytes and be a target for the modulation by female gonadal hormones.

Animals↗
PubMed1992

Tedisamil inhibits the delayed rectifier K+ current in single smooth muscle cells of the guinea-pig portal vein.

Tedisamil is a new bradycardic agent with an inhibitory action on K+ channels in cardiac muscle, and secondary beneficial effects in experimentally induced cardiac ischemia. In whole-cell clamp studies in enzymatically dispersed, single smooth muscle cells from the guinea-pig portal vein, tedisamil inhibited the delayed rectifier K+ current (determined as the charge transferred through the cell membrane), the mean concentration for half-maximal inhibition being 2.9 microM. In contrast to controls in the absence of drugs or in the presence of the classical K+ channel blockers barium, tetraethylammonium or 4-aminopyridine, the time course of the delayed rectifier K+ current in the presence of tedisamil could no longer be fitted by a single exponential, and signs of an accelerated inactivation by tedisamil were obtained. The slow onset of the response to tedisamil applied to the outside of the vascular myocytes, and the finding that tedisamil applied directly to the cytosol via the pipette was highly effective, suggest an intracellular site of action.

Animals↗
PubMed1997

Voltage dependent calcium and potassium currents in Y-1 adrenocortical cells are unresponsive to ACTH.

In this report we use both whole cell and perforated patch clamp recording techniques to characterize calcium and potassium channels in Y-1 adrenocortical cells in order to assess their responsiveness to ACTH. Both transient and long-lasting components of an inward calcium current were identified which were similar to T and L-type Ca2+ currents. With Ba2+ as the charge carrier, the transient current activated at voltages more hyperpolarized than -50 mV with V1/2 for activation at -78.1 mV, and for steady state inactivation at -52.3 mV. The L-type current activated at -20 mV, with a V1/2 for activation at -29.9 mV and steady state inactivation at -44.2 mV. Under perforated patch conditions the response was shifted to more depolarized voltages. Both currents were responsive to agents which usually affect T- or L-type Ca2+ currents. The transient current was completely blocked by 50 microM lanthanum or 200 microM nickel and partially blocked by 300 mM amiloride. Cadmium (100 microM) and nifedipine (300 nM) completely blocked the long-lasting current while omega-conotoxin GVIA (1992 nM) inhibited the current by only 20-25%. The agonist, Bay K 8644 was stimulatory at 50 nM. Both transient and sustained outward potassium currents similar to A-type and delayed rectifier currents, respectively, were present. The transient current demonstrated fast activation at voltages more positive than -10 mV, inactivation with continued depolarization and steady state inactivation at V1/2 = -50 mV. The sustained current activated rapidly and had minimal inactivation with continued depolarization. The transient current was blocked by 5 mM 4AP and the sustained by 25 mM TEA. While Y-1 cells contain both calcium and potassium currents similar to those found in other adrenocortical cells, none of the currents were affected by ACTH or AII, secretagogues which stimulate steroidogenesis. These data, combined with the inability of both Ca2+ and K+ channel blockers to alter ACTH-induced steroidogenesis as reported earlier, suggests that neither calcium nor potassium currents are responsive to ACTH in Y-1 cells.

Adrenal Cortex↗
PubMed1995

Analysis of the kinetics and voltage-dependency of transient and delayed K+ currents in muscle fibers isolated from the flatworm Schistosoma mansoni.

There are two distinct voltage-dependent K+ currents in muscle fibers freshly isolated from the human flatworm parasite S. mansoni. Present is a delayed rectifier current with a tau act of 17 msec and tau inact > 3 sec. The delayed rectifier is very resistant to steady-state inactivation, with over 40% of the current non-inactivating, and over 15 sec required for the maximum inactivation of the other portion. The current is resistant to block by extracellular tetraethylammonium, is half-blocked by 10 mM 4-aminopyridine, and is insensitive to dendrotoxin. Also present is an "A" current with tau act < 1 msec and tau inact < 15 msec. The "A" current, like the delayed rectifier current, is resistant to block by external tetraethylammonium and is insensitive to dendrotoxin. Three micromoles of 4-aminopyridine produce a half-blockade of the "A" current. These two K+ currents are very similar to a delayed rectifier and "A" currents that have been described in a number of lower and more advanced animals.

4-Aminopyridine↗
PubMed1998

Dispersion of ventricular repolarization in left ventricular hypertrophy: influence of afterload and dofetilide.

INTRODUCTION: Increased dispersion of ventricular repolarization is observed in cardiac hypertrophy and is associated with sudden cardiac death. At present, there is little information about the effects of cardiac hemodynamics and antiarrhythmic drugs on dispersion of repolarization in disease states. We compared the effects of increasing afterload and the Class III antiarrhythmic drug, dofetilide, on dispersion of ventricular repolarization in hypertrophied rabbit hearts to normal rabbit hearts. METHODS AND RESULTS: Cardiac hypertrophy was induced in rabbits by abdominal aortic banding. Isolated hearts were studied 49+/-4 days postsurgery in the working heart mode using a blood-buffer perfusate. The action potential duration (APD) was measured from eight sites on the epicardium of the heart at low (50+/-7 mmHg) afterload and high afterload (97+/-12 mmHg) at baseline and during dofetilide perfusion. APD dispersion, determined as the difference between the maximal and minimal APD, was greater in hypertrophied hearts (42+/-8 msec) compared with control hearts (26+/-8 msec, P < 0.05) at baseline and low afterload. Increasing afterload caused a decrease in APD dispersion in hypertrophied hearts (P < 0.05) but not in control hearts, and APD dispersion was similar in hypertrophied hearts (31+/-9 msec) compared with control hearts (30+/-9 msec, P = NS). During dofetilide perfusion, APD dispersion remained greater in hypertrophied hearts (60+/-39 msec) compared with control hearts (30+/-13 msec, P < 0.05) at low afterload but not high afterload. Increasing afterload caused shortening of the APD in most regions of the control hearts, whereas APD did not shorten significantly in hypertrophied hearts at baseline and tended to increase during dofetilide perfusion. During dofetilide perfusion, the maximal change in APD recorded from the posterior wall of the left ventricle following an increase in afterload was -18+/-21 msec in control hearts and 7+/-21 ms in hypertrophied hearts (P < 0.05). CONCLUSION: Epicardial APD dispersion decreases in hypertrophied hearts following an increase in afterload, and this response is mediated in part by the absence of afterload-induced shortening of the APD. This effect may be due in part to altered responses of the delayed rectifying current to cardiac loading conditions in the setting of cardiac hypertrophy.

Action Potentials↗
PubMed1976

Effects of glycerol treatment and maintained depolarization on charge movement in skeletal muscle.

1. Voltage-clamp experiments were carried out using the techniques described in the preceding paper. 2. In one series of experiments an attempt was made to disrupt the T-system with glycerol treatment. Muscles were soaked in Ringer + 400 mM glycerol for 1 hr at room temperature, transferred to Ringer + 5 mM calcium + 5 mM magnesium for 20-30 min, and then cooled to around 2 degrees C and placed in an isosmotic test solution containing tetrodotoxin for electrical measurements. 3. The density of charge seen in isosmotic tetraethylammonium (TEA) solution with strong depolarization, normalized according to fibre capacitance, was decreased by glycerol treatment to about one third the amount seen in untreated hypertonic fibres. 4. An analysis of fibre capacitance revealed that only 0-4 of the tubular capacitance was removed by this particular glycerol procedure. If the density of charge with respect to capacitance is corrected for this decrease in capacitance, the results indicate that glycerol treatment removed or immobilized 0-77 of the charge initially present. Thus the effect of glycerol treatment to reduce charge does not depend entirely on disrupting the electrical continuity of the T-system. 5. The effects of maintained depolarization were studied using a TEA Ringer made hypertonic with sucrose. When the voltage was changed from -80 to -21 mV the measurable charge movement declined exponentially to zero with a time constant of 13-24 sec. On repolarization the process recovered exponentially to the initial level with a time constant of 21-53 sec. 6. Experiments were also carried out using a sodium Ringer made hypertonic with sucrose. For small depolarizations only charge movement currents were seen, whereas for large depolarizations large delayed ionic currents, presumably carried by potassium, were observed. With moderate depolarizations in the range V = -40 to -30 mV, both components were of comparable magnitude. 7. A plot of the fractional charge movement (Q/Qmax) vs. V fitted at moderate depolarizations is similar to that of n infinity vs. V fitted at larger depolarizations. Values of n infinity were obtained by fitting the delayed ionic current to n4(V - VK). For voltages between -40 and -30 mV the time constant for charge tauQ was always less than taun; values of taun/tauQ varied from 1-6 to 4-3. 8. Glycerol treatment had little if any effect on the kinetics of delayed rectifier currents. Values of gK measured in isosmotic solution following glycerol were about one third the values obtained in untreated fibres in a hypertonic solution (osmolality three times normal). The threefold difference in gK is probably due to a similar difference in internal potassium concentration. 9. These results and others are difficult to reconcile with the idea that the charge movement process acts as a gate for potassium channels. It seems more likely that charge movement is a step in the activation of contraction.

Animals↗
PubMed1999

[Characteristics of outward potassium currents of outer hair cell isolated from the guinea pig cochlea].

OBJECTIVE: To study the normal values and characteristics of potassium currents (Ik) of outer hair cell (OHC) isolated from the guinea pig cochlea. METHOD: With the patch-clamp whole cell recording technique and several supplementary methods, the Ik potassium tail current (Iktail) and reverse potential were recorded under the conditions of the various intra and extracellular solutions and various command voltage stimuli. RESULT: Ik possessed evident voltage and time-dependence. The peak current appeared within 20 ms. The average activated potential was approximately -32.7 mV. Ik increased fastestly and greatestly in the voltage range from the activating voltage to 0 mV, and it approached saturation approximately at 40 mV. In normal status, no distinct "rundown phenomenon" of Ik appeared. When 10 mmol/L KCl was put in extracellular solution, Ik would increased. Nevertheless, when K+ was substituted by Cs+ in the intracellular solution, Ik would disappear. The reversal potential, -64.0 mV in average approximately, could be measured by means of Iktail. Furthermore, by means of slope command voltage stimuli, the processes of Ik activation, increment or decrement and saturation could be observed. CONCLUSION: As showing by the above described features, Ik possessed the characteristics of both an inward rectifier and rapid element of a delay rectifier, which would play important role in frequency tuning, mechanic-electrical transduction, maintenance of resting potential and excitement in OHC.

Animals↗
PubMed1997

Outward potassium currents of supraoptic magnocellular neurosecretory cells isolated from the adult guinea-pig.

1. Several types of whole-cell outward K+ current recorded from magnocellular neurosecretory cells (MNCs) dissociated from the supraoptic nucleus of the adult guinea-pig were identified on the basis of their voltage dependence, kinetics, pharmacology and Ca2+ dependence. 2. The predominant K+ current evoked from a holding potential of -40 mV was slowly activating, long-lasting, tetraethylammonium (TEA) sensitive and showed little steady-state inactivation. Also, this current was reduced by extracellular Cd2+. These data suggest that in supraoptic MNCs classical Ca(2+)-insensitive, delayed rectifier channels (KV) and Ca(2+)-sensitive, non-inactivating channels (KCa) both contribute to the sustained current. 3. A transient, low-threshold K+ current, which was 4-aminopyridine (4-AP) sensitive and showed significant steady-state inactivation, was evoked along with the sustained current from a holding potential of -90 mV. Based on these characteristics, this current corresponds to the A-current (IK(A)) described in other neurons. 4. IK(A) was activated when Ca2+ influx was blocked or when Ca2+ was absent from the extracellular medium, suggesting that Ca2+ influx is not necessary for activation of the current. 5. In many recordings, a transient 4-AP-insensitive outward current was evoked from a holding potential of -40 mV. This high-threshold transient K+ current was abolished by extracellular Cd2+ or TEA and was absent when extracellular Ca2+ was replaced by Sr2+, suggesting that it is a transient Ca(2+)-dependent K+ current. 6. We conclude that the presence of multiple types of K+ current may, in part, underlie the complex firing patterns of oxytocinergic and vasopressinergic MNCs.

4-Aminopyridine↗
PubMed1995

Potassium currents in human freshly isolated bronchial smooth muscle cells.

1. K+ currents were studied in smooth muscle cells enzymatically dissociated from human bronchi, by use of the patch-clamp technique. 2. In whole-cell recordings a depolarization-induced, 4-aminopyridine (4-AP)-sensitive current was observed in only 26 of 155 cells, and in 20 of these 26 cells its amplitude at a test potential of 0 mV was less than 100 pA. 3. In the majority of cells depolarization to -40 mV or more positive potentials induced a noisy outward current which activated within milliseconds and showed almost no inactivation even during a 5 s depolarizing voltage step. This current was insensitive to 4-AP (up to 5 mM) but was strongly inhibited in the presence of tetraethylammonium (TEA, 1 mM), charybdotoxin (ChTX, 100 nM) or iberiotoxin (IbTX, 50 nM) in the bath. The same current was also recorded by the nystatin-perforated patch technique. 4. Single channels with a conductance of about 210 pS were recorded in cell-attached patch, inside-out patch, outside-out patch and whole-cell recording configurations. Channel open state probability in inside-out patches was 0.5 at a membrane potential of 4 +/- 14 mV (mean +/- s.d., n = 13) mV even with a free Ca2+ concentration on the cytosolic side of the patch of less than 0.1 nM. Open state probability increased with depolarization and internal Ca2+ concentration. Single channels could be reversibly blocked by externally applied TEA, ChTX and IbTX. 5. In current-clamp recordings with 100 nM free Ca2+ in the intracellular solution both TEA and ChTX caused substantial concentration-dependent depolarization. 6. These results suggest that in human bronchial smooth muscle cells, in marked contrast to other species, the majority of the outward current induced by depolarization is not due to a delayed rectifier,but to the activity of a large conductance, ChTX-sensitive K+ channel. The Ca2+- and voltage-dependency of this channel may well allow a sufficiently high open state probability for it to play a partin the regulation of the resting membrane potential.

Adult↗
PubMed1998

Potassium channels in human fetal airway smooth muscle cells.

Ion channels underlying the resting membrane potential were examined in human fetal airway smooth muscle (ASM). Tissue was obtained from the Medical Research Council Tissue Bank, London, UK. ASM cells were enzymatically dispersed, and ion currents were examined using a patch clamp. Although all cells were of similar size and stained intensely for vimentin, only approximately 50% stained intensely for smooth muscle alpha-actin or myosin heavy chain. Depolarization induced a tetraethylammonium (TEA)- and charybdotoxin (ChTX)-sensitive outward current that varied widely among cells (<50 to >2000 pA at +100 mV), and a smaller nonselective cation current that was similar in all cells (approximately 20 pA at +100 mV). The TEA-sensitive current was associated with three types of large conductance, ChTX-sensitive K+ channel: a 200-pS channel, which was active at negative potentials and low [Ca2+], as described for freshly isolated adult ASM, and two other K+ channels of 100 and 150 pS, previously observed only in adult ASM proliferating in culture. ChTX, but not 4-aminopyridine, caused a substantial depolarization in the current clamp mode, suggesting that, in contrast to ASM from other species or vascular smooth muscle, large conductance K+ channels rather than a delayed rectifier are the major determinant of membrane potential in this tissue. Our results show a distinct similarity between fetal ASM and adult ASM proliferating in culture. We suggest that the heterogeneity in current density and staining reflect different degrees of differentiation, rather than different cell types, and that the 100- and 150-pS K+ channels are specifically associated with a proliferative phenotype in human ASM.

Abortion, Induced↗
PubMed1993

Effects of MS-551, a new class III antiarrhythmic drug, on action potential and membrane currents in rabbit ventricular myocytes.

1. Electrophysiological effects of MS-551, a new class III antiarrhythmic drug, were examined and compared with those of (+)-sotalol in rabbit ventricular cells. 2. In rabbit ventricular muscles stimulated at 1.0 Hz, MS-551 (0.1-10 microM) and (+)-sotalol (3-100 microM) prolonged action potential duration (APD) and effective refractory period without affecting the maximum upstroke velocity of phase 0 depolarization (Vmax). The class III effect of MS-551 was approximately 30 times more potent than that of (+)-sotalol. 3. Class III effects of MS-551 and (+)-sotalol showed reverse use-dependence, i.e., a greater prolongation of APD at a longer cycle length. 4. In rabbit isolated ventricular cells, 3 microM MS-551 and 100 microM sotalol inhibited the delayed rectifier potassium current (IK) which was activated at more positive potentials than -50 mV and saturated around +20 mV. 5. MS-551 at a higher concentration of 10 microM decreased the transient outward current (Ito) and the inward rectifier potassium current (IK1) although 100 microM sotalol failed to inhibit these currents. 6. MS-551 is a non-specific class III drug which can inhibit three voltage-gated K+ channels in rabbit ventricular cells.

Action Potentials↗
PubMed2004

Pharmacology of cardiac potassium channels.

Cardiac K+ channels are membrane-spanning proteins that allow the passive movement of K+ ions across the cell membrane along its electrochemical gradient. They regulate the resting membrane potential, the frequency of pacemaker cells and the shape and duration of the cardiac action potential. Additionally, they have been recognized as potential targets for the actions of neurotransmitters and hormones and class III antiarrhythmic drugs that prolong the action potential duration (APD) and refractoriness and have been found effective to prevent/suppress cardiac arrhythmias. In the human heart, K+ channels include voltage-gated channels, such as the rapidly activating and inactivating transient outward current (Ito1), the ultrarapid (IKur), rapid (IKr) and slow (IKs) components of the delayed rectifier current and the inward rectifier current (IK1), the ligand-gated channels, including the adenosine triphosphate-sensitive (IKATP) and the acetylcholine-activated (IKAch) currents and the leak channels. Changes in the expression of K+ channels explain the regional variations in the morphology and duration of the cardiac action potential among different cardiac regions and are influenced by heart rate, intracellular signalling pathways, drugs and cardiovascular disorders. A progressive number of cardiac and noncardiac drugs block cardiac K+ channels and can cause a marked prolongation of the action potential duration (i.e. an acquired long QT syndrome, LQTS) and a distinct polymorphic ventricular tachycardia termed torsades de pointes. In addition, mutations in the genes encoding IKr (KCNH2/KCNE2) and IKs (KCNQ1/KCNE1) channels have been identified in some types of the congenital long QT syndrome. This review concentrates on the function, molecular determinants, regulation and, particularly, on the mechanism of action of drugs modulating the K+ channels present in the sarcolemma of human cardiac myocytes that contribute to the different phases of the cardiac action potential under physiological and pathological conditions.

Action Potentials↗
PubMed1995

Inhibition of delayed rectifier K(+)-current by levcromakalim in single intestinal smooth muscle cells: effects of cations and dependence on K(+)-flux.

1. Whole-cell voltage-clamp recordings were made from single smooth muscle cells isolated from the longitudinal layer of the guinea-pig small intestine. 2. Levcromakalim ((-)Ckm) inhibited delayed rectifier K-current (IK(DR)) and induced a voltage-independent K-current (IK(-Ckm)). Both effects were inhibited similarly by glibenclamide. In some cells, however, IK(-Ckm) could be induced without any effect on IK(DR). 3. Ba2+ caused a voltage-dependent block of IK(-Ckm). The IC50 was 0.2 mM at -40 mV (6 cells), but at 0 mV 2 mM Ba2+ caused only a 26 +/- 7% inhibition (n = 5). Ba2+ had much less effect on IK(DR), 2 mM Ba2+ having no inhibitory effect on current elicited by depolarization to -30 mV (n = 6) or 0 mV (n = 5). 4. Low concentrations of Zn2+ blocked IK(-Ckm) while having little effect on IK(DR). Zn2+ (40 microM) caused a 77 +/- 1% reduction of IK(-Ckm) at -30 mV (n = 4) but IK(DR) was inhibited by only 10 +/- 3% at the same voltage (n = 4). 5. Inward current amplitudes were compared in 135 mM Rb+ and 135 mM K+ bath solutions. (-)Ckm-activated Rb(+)-current was only 4% of the K(+)-current, whereas delayed rectifier Rb(+)-current was larger than K(+)-current. 6. (-)Ckm did not inhibit IK(DR) if IK(-Ckm) was blocked. In the presence of 2 mM Ba2+ or 135 mM Rb+, (-)Ckm did not induce current nor did it inhibit the delayed rectifier. When [Rb+]o was 25 mM and [K+]J was 130 mM, (-)Ckm elicited outward current and inhibited outward delayed rectifier current (at voltages positive of the reversal potential) but it did not elicit inward current or inhibit inward delayed rectifier current (at voltages negative of the reversal potential).7. These experiments indicate that (-)Ckm-activated K channels are more sensitive to inhibition by Ba2+and Zn2+ and pass inward Rb+ current less well than delayed rectifier K channels. They also suggest that (-)Ckm does not modulate delayed rectifier K channels directly or via an intermediate protein but that the inhibitory effect of (-)Ckm on IK(DR) arises as a consequence of K+-flux through (-)Ckm activated K channels.

Animals↗
PubMed1988

Characterization of membrane currents in dissociated adult rat pineal cells.

1. Membrane currents, particularly the outward components, were studied in pineal cells acutely dissociated from adult rats using the whole-cell variant of the patch-clamp technique. 2. In current clamp, outward constant current elicited a transient graded depolarizing response. A sustained membrane rectification developed within 20 ms; this phenomenon was reduced in cells internally dialysed with 120 mM-CsCl. 3. Study of the membrane current revealed the existence of a transient and a delayed outward current. These currents were virtually eliminated when the cell was internally dialysed with CsCl. 4. The delayed outward current, isolated from a holding potential of -50 mV, activated at potentials near -20 mV, reached a steady-state current amplitude within 60 ms and had little or no decay during steps up to 400 ms in duration. This component was reduced by 80% or more with the addition of 5 mM-TEA. 5. From -100 mV, the transient outward current reached a peak within 15 ms and decayed with a single-exponential time course. The mean decay time constant was 66 +/- 10 ms (at -33 mV) and it showed little voltage sensitivity. This current, which activated at potentials positive to -60 mV and displayed half-inactivation at -76 +/- 8 mV, was reduced by 50% with the addition of 5 mM-4-AP (4-amino-pyridine). 6. In the presence of external Ca2+, the current-voltage relationship for the delayed current did not display a region of negative-slope conductance (N-shape). Increasing the intracellular ionized Ca2+ concentration by varying the Ca-EGTA buffer ratio did not alter the dependence of the current on the membrane potential. 7. Block of outward currents with internal Cs+ revealed a small (less than 90 pA) inward Ca2+ current when the external Ca2+ concentration was increased to 10 mM. From a holding potential of -50 mV, it had a threshold at -30 mV and peaked at +5 mV. Evidence for an inward Na+ current was not obtained. 8. We conclude that acutely dissociated pineal cells display two distinct K+ currents: (i) a slowly activating, sustained current similar to the delayed rectifier (IK); and (ii) a transient A-current (IA). At normal Ca2+ concentrations, no macroscopic Ca2+-activated outward current was observed.

4-Aminopyridine↗
PubMed1993

Shaker-related potassium channel, Kv1.4, mRNA regulation in cultured rat heart myocytes and differential expression of Kv1.4 and Kv1.5 genes in myocardial development and hypertrophy.

The multiple K+ channels are crucial for repolarization and configuration of the action potential in the neuronal and cardiac cells. In this study, we report the regulatory mechanisms of rapidly inactivating Shaker Kv1.4 channel transcript in the rat heart. Quantitative PCR analysis showed that stimulation with high concentration of KCl, BAY-K 8644, or 12-O-tetradecanoyl phorbol-13-acetate resulted in an immediate and substantial increase (two- to threefold) of Kv1.4 mRNA levels in spontaneously beating myocytes prepared from neonatal rat ventricles. The Kv1.4 mRNA in the ventricle remains at a steady state level after birth and gradually declines with maturation. These results suggest that the Kv1.4 mRNA level is not static and undergoes dynamic modulation by multiple factors that activate intracellular signals. In addition, the expression patterns of Kv1.4 as well as the delayed rectifier Shaker K+ channel Kv1.5 mRNAs were examined in hypertrophied ventricles in which a plateau phase of action potential is remarkably prolonged. The Kv1.5 mRNA level was dramatically repressed while the Kv1.4 mRNA level was remarkably increased. This differential regulation was completely reversed by the normalization of hypertrophy, suggesting that the pathological alterations of K+ channel gene regulation may be involved in the occurrence of ventricular arrhythmias in hypertrophic hearts.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole.

The widely used histamine receptor antagonists terfenadine and astemizole were shown to prolong the QT interval in electrocardiographic recordings in cases of overdose or inappropriate co-medications, indicating a possible interaction with cardiac K+ channels. Here, terfenadine and astemizole both inhibited the human ether-a-go-go related gene (HERG) encoded channels expressed in Xenopus oocytes at nanomolar concentrations in a use- and voltage-dependent fashion. In contrast, inhibition of other delayed rectifier (Kv1.1 and IsK) or inward rectifier K+ channels (IRK1) was much weaker and occurred only at high micromolar concentrations. These results suggest that blockade of HERG channels by terfenadine and astemizole might contribute to the cardiac side effects of these compounds.

Animals↗